Biodegradable triblock copolymers for implantable devices

ABSTRACT

The present invention is directed to polymeric materials made of biodegradable, bioabsorbable triblock copolymers and implantable devices (e.g., drug-delivery stents) containing such polymeric materials. The polymeric materials may also contain at least one therapeutic substance. The polymeric materials are formulated so as to improve the mechanical and adhesion properties, degradation, biocompatibility and drug permeability of such materials and, thus, implantable devices formed of such materials.

BACKGROUND

1. Field of the Invention

The present invention is directed to polymeric materials made ofbiodegradable, bioabsorbable triblock copolymers and implantable devices(e.g., drug-delivery stents) containing such polymeric materials.

2. Description of the State of the Art

Angioplasty is a well-known procedure for treating heart disease. Aproblem associated with angioplasty includes formation of intimal flapsor torn arterial linings which can collapse and occlude the conduitafter the balloon is deflated. Moreover, thrombosis and restenosis ofthe artery may develop over several months after angioplasty, which mayrequire another angioplasty procedure or a surgical by-pass operation.“Stenosis” refers to a narrowing or constriction of the diameter of abodily passage or orifice, and “restenosis” refers to the reoccurrenceof stenosis in a blood vessel or heart valve after it has been treated(as by balloon angioplasty, stenting, or valvuloplasty) with apparentsuccess.

Stents are often used in the treatment of atherosclerotic stenoses inblood vessels. To reduce the partial or total occlusion of the artery bythe collapse of arterial lining and to reduce the chance of thrombosisand restenosis following angioplasty in the vascular system, a stent maybe implanted in the lumen to reinforce body vessels and maintain thevascular patency. A “lumen” refers to a cavity of a tubular organ suchas a blood vessel. As a mechanical intervention, stents act asscaffoldings, functioning to physically hold open and, if desired, toexpand the wall of a passageway, e.g., a blood vessel, urinary tract orbile duct.

Stents are also used as a vehicle for providing biological therapy.Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site, thereby possibly avoiding side effects associatedwith systemic administration of such medication. One method ofmedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent, in which a therapeutic substance is impregnatedin polymer.

Late stent thrombosis has emerged as a concern for drug-delivery stents.The incidence of late stent thrombosis appears to be higher withdrug-delivery stents than with the corresponding bare metal stents. Onepotential cause of late thrombosis with drug-delivery stents is achronic inflammatory or hypersensitivity response to the polymericcoating on the stent.

The present invention addresses late stent thrombosis and offers otheradvantageous features.

SUMMARY OF THE INVENTION

The present invention is directed to biodegradable polymeric materialsused for implantable devices (e.g., stents) that enable the devices toperform their functions more effectively and avoid adverse effects. Thepolymeric materials are configured to completely or substantiallycompletely erode after the devices accomplish their intended functions(e.g., maintaining vascular patency and locally delivering drugs),thereby avoiding adverse effects such as late stent thrombosis. Otheradvantages of the biodegradable polymeric materials include, amongothers, good mechanical properties (e.g., strength, rigidity, toughnessand flexibility), control of drug-release rates, and enhanced adhesionto metal surfaces.

One embodiment of the invention is directed to a composition comprisinga biodegradable triblock copolymer of the structure A-B-A′, wherein:

-   -   the A and A′ blocks each independently are hard blocks having a        T_(g) or T_(m) above body temperature;    -   the B block is a soft block having a T_(g) less than the T_(g)        or T_(m) of the A and A′ blocks;    -   the A, B and A′ blocks each independently have a polymer        number-average molecular weight (M_(n)) from about 1 kDa to        about 500 kDa; and    -   the A and A′ blocks may be the same or different.

In another embodiment, the tensile modulus of the hard A and A′ blocksindependently is greater than about 1,000 MPa, and the tensile modulusof the soft B block is less than about 1,000 MPa. In yet anotherembodiment, the weight fraction of the A and A′ blocks is from about 1%to about 99% of the triblock copolymer. In still another embodiment, theA, B and A′ blocks each independently comprise a polymer comprising fromone to four different types of monomer, wherein each type of monomer hasfrom about 5 to about 5,000 monomer units.

In a further embodiment of the ABA′ triblock copolymers:

-   -   the A and A′ blocks each independently comprise a polymer        selected from the group consisting of poly(L-lactide) (PLLA),        poly(D,L-lactide), poly(glycolide) (PGA),        poly(GA-co-D,L-lactide), poly(GA-co-L-lactide), and any        variations in the arrangement of the monomers thereof, and    -   the B block comprises a polymer selected from the group        consisting of poly(caprolactone) (PCL), poly(CL-co-GA),        poly(trimethylene carbonate) (PTMC), poly(TMC-co-GA),        poly(TMC-co-D,L-lactide), poly(TMC-co-L-lactide),        poly(TMC-co-CL), poly(TMC-co-D,L-lactide-co-GA),        poly(TMC-co-CL-co-GA), poly(dioxanone), poly(TMC-co-dioxanone),        poly(dioxanone-co-CL), poly(dioxanone-co-D,L-lactide),        poly(dioxanone-co-L-lactide), poly(dioxanone-co-GA),        poly(dioxanone-co-D,L-lactide-co-GA), polyketals, and any        variations in the arrangement of the monomers thereof.

According to an embodiment, the polyketal polymer of the B block has thestructure

wherein R₁ is a poly(caprolactone) diol or a C₂-C₂₄ diol of thestructure, HO—R₁—OH, that contains an optionally substituted aliphatic,heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic orheteroaromatic group, or a combination thereof, and n is an integer fromabout 5 to about 5,000.

In yet another embodiment, at least one dihydroxyaryl group isconjugated to the polymer ends of the triblock copolymer.

In still another embodiment, the composition of the invention furthercomprises at least one biocompatible moiety.

In a further embodiment, the composition further comprises at least oneadditional biologically absorbable polymer.

In some embodiments, the composition further comprises at least onebiologically active agent. In an embodiment, the at least onebiologically active agent is selected from the group consisting ofantiproliferative, antineoplastic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antiallergic and antioxidant substances.

According to another embodiment, the at least one biologically activeagent is selected from the group consisting of paclitaxel, docetaxel,estradiol, nitric oxide donors, super oxide dismutases, super oxidedismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N-tetrazolyl)-rapamycin (zotarolimus), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, progenitor cell-capturing antibodies,prohealing drugs, prodrugs thereof, co-drugs thereof, and a combinationthereof.

Other embodiments of the invention are directed to a coating comprisingany combination of embodiments of the inventive composition.

Yet other embodiments of the invention are directed to an implantabledevice formed of a material comprising any combination of embodiments ofthe inventive composition. In an embodiment, the material comprises anycombination of embodiments of the inventive coating, which is disposedover the implantable device. In another embodiment, the implantabledevice is a stent, graft, stent-graft, catheter, lead, electrode, clip,shunt, closure device, or valve.

Still other embodiments of the invention are directed to a method ofpreparing any combination of embodiments of the inventive composition,e.g., via ring-opening polymerization of the corresponding monomers ofthe A, B and A′ blocks.

Further embodiments of the invention are directed to a method offabricating an implantable device. In one embodiment, the methodcomprises forming the implantable device of a material comprising anycombination of embodiments of the inventive composition. In anotherembodiment, the method comprises depositing any combination ofembodiments of the inventive coating over at least a portion of theimplantable device. In some embodiments, the implantable device is astent, graft, stent-graft, catheter, lead, electrode, clip, shunt,closure device, or valve.

Still further embodiments of the invention are directed to a method oftreating or preventing a condition or disorder in a patient, comprisingimplanting in the patient any combination of embodiments of theinventive implantable device. In an embodiment, the condition ordisorder is selected from the group consisting of atherosclerosis,thrombosis, restenosis, hemorrhage, vascular dissection, vascularperforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, patent foramen ovale, claudication, anastomotic proliferationof vein and artificial grafts, bile duct obstruction, ureter obstructionand tumor obstruction.

Various embodiments of the invention are described in further detailbelow.

DETAILED DESCRIPTION OF THE INVENTION Terms and Definitions

The following definitions apply:

The terms “biologically degradable” (or “biodegradable”), “biologicallyerodable” (or “bioerodable”), “biologically absorbable” (or“bioabsorbable”), and “biologically resorbable” (or “bioresorbable”), inreference to polymers and coatings, are used interchangeably and referto polymers and coatings that are capable of being completely orsubstantially completely degraded, dissolved, and/or eroded over timewhen exposed to bodily fluids such as blood and can be graduallyresorbed, absorbed and/or eliminated by the body, or that can bedegraded into fragments that can pass through the kidney membrane of ahuman (e.g., fragments having a molecular weight of about 40,000 Daltons(40 kDa) or less). The process of breaking down and eventual absorptionand elimination of the polymer or coating can be caused by, e.g.,hydrolysis, metabolic processes, oxidation, enzymatic processes, bulk orsurface erosion, and the like. Conversely, a “biostable” polymer orcoating refers to a polymer or coating that is not biodegradable.

Whenever the reference is made to “biologically degradable,”“biologically erodable,” “biologically absorbable,” and “biologicallyresorbable” stent coatings or polymers forming such stent coatings, itis understood that after the process of degradation, erosion,absorption, and/or resorption has been completed or substantiallycompleted, no coating or substantially little coating will remain on thestent. Whenever the terms “degradable,” “biodegradable,” or“biologically degradable” are used in this application, they areintended to broadly include biologically degradable, biologicallyerodable, biologically absorbable, and biologically resorbable polymersor coatings.

“Biodegradability,” “bioerodability,” “bioabsorbability,” and“bioresorbability” are defined as inherent property of the coating orpolymer forming the coating that is biologically degradable,biologically erodable, biologically absorbable, or biologicallyresorbable.

As used herein, “biocompatible” moieties refer to moieties that arecapable of enhancing biological compatibility of the composition,material or structure containing them.

“Physiological conditions” refer to conditions to which an implant isexposed within the body of an animal (e.g., a human). Physiologicalconditions include, but are not limited to, human body temperature(approximately 37° C.) and an aqueous environment of physiologic ionicstrength, pH and enzymes.

In the context of a blood-contacting implantable device, a “prohealing”drug or agent refers to a drug or agent that has the property that itpromotes or enhances re-endothelialization of arterial lumen to promotehealing of the vascular tissue.

As used herein, a “co-drug” is a drug that is administered concurrentlyor sequentially with another drug to achieve a particularpharmacological effect. The effect may be general or specific. Theco-drug may exert an effect different from that of the other drug, or itmay promote, enhance or potentiate the effect of the other drug.

As used herein, the term “prodrug” refers to an agent rendered lessactive by a chemical or biological moiety, which metabolizes into orundergoes in vivo hydrolysis to form a drug or an active ingredientthereof. The term “prodrug” can be used interchangeably with terms suchas “proagent”, “latentiated drugs”, “bioreversible derivatives”, and“congeners”. N.J. Harper, Drug latentiation, Prog Drug Res., 4: 221-294(1962); E. B. Roche, Design of Biopharmaceutical Properties throughProdrugs and Analogs, Washington, D.C.: American PharmaceuticalAssociation (1977); A. A. Sinkula and S. H. Yalkowsky, Rationale fordesign of biologically reversible drug derivatives: prodrugs, J. Pharm.Sci., 64: 181-210 (1975). Use of the term “prodrug” usually implies acovalent link between a drug and a chemical moiety, though some authorsalso use it to characterize some forms of salts of the active drugmolecule. Although there is no strict universal definition of a prodrugitself, and the definition may vary from author to author, prodrugs cangenerally be defined as pharmacologically less active chemicalderivatives that can be converted in vivo, enzymatically ornonenzymatically, to the active, or more active, drug molecules thatexert a therapeutic, prophylactic or diagnostic effect. Sinkula andYalkowsky, above; V. J. Stella et al., Prodrugs: Do they have advantagesin clinical practice?, Drugs, 29: 455-473 (1985).

The terms “block copolymer” and “graft copolymer” are defined inaccordance with the terminology used by the International Union of Pureand Applied Chemistry (IUPAC). “Block copolymer” refers to a copolymercontaining a linear arrangement of blocks. The block is defined as aportion of a polymer molecule in which the monomer units have at leastone constitutional or configurational feature absent from the adjacentportions. “Graft copolymer” refers to a polymer composed ofmacromolecules with one or more species of block connected to the mainchain as side chains, these side chains having constitutional orconfigurational features that differ from those in the main chain.

The term “ABA′ triblock copolymer” is defined as a block copolymerhaving moieties A, B and A′ arranged according to the general formula-{[A-]_(m)-[B]_(n)-[A′]_(p)}-_(x), where each of “m,” “n,” “p” and “x”independently is a positive integer ≧1. For example, each of m, n, and pindependently may be ≧1 and ≦10,000.

The blocks of the ABA′ triblock copolymer need not be linked on theends, since the values of the integers determining the number of A, Band A′ blocks are such as to ensure that the individual blocks areusually long enough to be considered polymers in their own right.Accordingly, the ABA′ triblock copolymer can be named poly A-block-polyB-block-poly A′ block copolymer. Blocks A, B and A′ can be alternatingor random.

As used herein, a material that is described as a coating “disposedover” an indicated substrate, e.g., an implantable device, refers to acoating of the material deposited directly or indirectly over at least aportion of the surface of the substrate. Direct depositing means thatthe coating is applied directly to the exposed surface of the substrate.Indirect depositing means that the coating is applied to an interveninglayer that has been deposited directly or indirectly over the substrate.

As used herein, an “implantable device” may be any device that can beimplanted in an animal. Examples of implantable devices include, but arenot limited to, self-expandable stents, balloon-expandable stents,coronary stents, peripheral stents, stent-grafts, catheters, otherexpandable tubular devices for various bodily lumen or orifices, grafts,vascular grafts, arterio-venous grafts, by-pass grafts, pacemakers anddefibrillators, leads and electrodes for the preceding, artificial heartvalves, anastomotic clips, arterial closure devices, patent foramenovale closure devices, and cerebrospinal fluid shunts. The stents may beintended for any vessel in the body, including neurological, carotid,vein graft, coronary, aortic, renal, iliac, femoral, poplitealvasculature, and urethral passages. An implantable device can bedesigned for the localized delivery of a therapeutic agent. A medicatedimplantable device may be constructed by coating the device or substratewith a coating material containing a therapeutic agent. The substrate ofthe device may also contain a therapeutic agent. An implantable devicecan be fabricated with a coating containing partially or completely abiodegradable/bioabsorbable/bioerodable polymer, a biostable polymer, ora combination thereof. An implantable device itself can also befabricated partially or completely from abiodegradable/bioabsorbable/bioerodable polymer, a biostable polymer, ora combination thereof.

The “glass transition temperature”, T_(g), is the temperature at whichthe amorphous domains of a polymer change from a brittle, glassy,vitreous state to a solid deformable, ductile or rubbery state atatmospheric pressure. In other words, the T_(g) corresponds to thetemperature where the onset of segmental motion in the chains of thepolymer occurs. When an amorphous or semicrystalline polymer is exposedto an increasing temperature, the coefficient of expansion and the heatcapacity of the polymer both increase as the temperature is raised,indicating increased molecular motion. As the temperature is raised, theactual molecular volume in the sample remains constant, and so a highercoefficient of expansion points to an increase in free volume associatedwith the system and therefore increased freedom for the molecules tomove. The increasing heat capacity corresponds to an increase in heatdissipation through movement. The T_(g) of a given polymer can bedependent on the heating rate and can be influenced by the thermalhistory of the polymer. Furthermore, the chemical structure of thepolymer heavily influences the glass transition by affecting chainmobility.

The “melting temperature”, T_(m), is the temperature at which thecrystalline domains of a polymer lose their short- and long-term order,changing from a regular, ordered structure of chain packing to that of adisordered structure, resembling an amorphous polymer. The disappearanceof the polymer crystalline phase is accompanied by changes in physicalproperties of the polymer. The material becomes a viscous solid, withdiscontinuous changes in the density, refractive index, heat capacity,transparency, and other properties. The T_(m) of a given polymer occursover a finite temperature range. The breadth of the transition isdependent on the size and perfection of the polymer crystallites, aswell as their homogeneity and purity. By thermal analytical techniques,the T_(m) of a semi-crystalline polymer is an endothermic transitionwhen the heating rate is positive. The ability of the polymer chains topack into an ordered, repeating structure is heavily influenced by thechemical structure of the polymer.

“Stress” refers to force per unit area, as in the force acting through asmall area within a plane. Stress can be divided into components, normaland parallel to the plane, called normal stress and shear stress,respectively. True stress denotes the stress where force and area aremeasured at the same time. Conventional stress, as applied to tensionand compression tests, is force divided by the original gauge length.

“Strength” refers to the maximum stress along an axis which a materialwill withstand prior to fracture. The ultimate strength is calculatedfrom the maximum load applied during the test divided by the originalcross-sectional area.

“Modulus” may be defined as the ratio of a component of stress or forceper unit area applied to a material divided by the strain along an axisof applied force that results from the applied force. For example, amaterial has both a tensile and a compressive modulus. A material with arelatively high modulus tends to be stiff or rigid. Conversely, amaterial with a relatively low modulus tends to be flexible. The modulusof a material depends on the molecular composition and structure,temperature of the material, amount of deformation, and the strain rateor rate of deformation. For example, below its T_(g), a polymer tends tobe brittle with a high modulus. As the temperature of a polymer isincreased from below to above its T_(g), its modulus decreases.

“Strain” refers to the amount of elongation or compression that occursin a material at a given stress or load.

“Elongation” may be defined as the increase in length in a materialwhich occurs when subjected to stress. It is typically expressed as apercentage of the original length.

“Toughness” is the amount of energy absorbed prior to fracture, orequivalently, the amount of work required to fracture a material. Onemeasure of toughness is the area under a stress-strain curve from zerostrain to the strain at fracture. Thus, a brittle material tends to havea relatively low toughness.

The terms “alkyl” and “aliphatic group” refer to an optionallysubstituted, straight-chain or branched, saturated or unsaturatedhydrocarbon moiety that may contain one or more heteroatoms selectedfrom O, S, and N. If unsaturated, the alkyl or aliphatic group maycontain one or more double bonds and/or one or more triple bonds. Thealkyl or aliphatic group may be monovalent (i.e., —R) or divalent (i.e.,—R—) in terms of its attachment to the rest of the compound. Examples ofalkyl and aliphatic groups include, but are not limited to, methyl,ethyl, ethylenyl, ethynyl, n-propyl, isopropyl, propenyl, propynyl,n-butyl, isobutyl, sec-butyl, tertiary-butyl, butenyl, butynyl,n-pentyl, isopentyl, pentenyl, and pentynyl.

The terms “heteroalkyl” and “heteroaliphatic group” refer to an alkyl oraliphatic group that contains at least one heteroatom selected from O, Sand N, in the main portion and/or the branch(es) of the hydrocarbonmoiety. Examples of heteroalkyl and heteroaliphatic groups include, butare not limited to, alcohols, ethers, oxo compounds, ketones, aldehydes,esters, carbonates, thioesters, thiols, sulfides, sulfoxides, sulfones,sulfonamides, amino compounds, amines, nitriles, N-oxides, imines,oximes, amides, carbamates, ureas, and thioureas.

The terms “cycloalkyl” and “cycloaliphatic group” refer to an optionallysubstituted, saturated or unsaturated, mono- or polycyclic hydrocarbonmoiety that may contain one or more heteroatoms selected from O, S, andN. If unsaturated, the cycloalkyl or cycloaliphatic group may containone or more double bonds and/or one or more triple bonds in and/or offof one or more rings of the cyclic moiety. The cycloalkyl orcycloaliphatic group may be monovalent (i.e., -Cyc) or divalent (i.e.,-Cyc-) in terms of its attachment to the rest of the compound. Examplesof cycloalkyl and cycloaliphatic groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, decahydronaphthyl, and octahydroindyl.

The terms “heterocycloalkyl” and “heterocycloaliphatic group” refer to acycloalkyl or cycloaliphatic group in which at least one ring in thecyclic moiety contains one or more heteroatoms selected from O, S, andN. Examples of heterocycloalkyl and heterocycloaliphatic groups include,but are not limited to, aziridinyl, oxiranyl, oxolanyl, thiolanyl,pyrrolidinyl, 3-pyrrolinyl, dioxalanyl, 1,3-dithiolanyl, oxazolidinyl,imidazolidinyl, oxanyl, piperidinyl, piperazinyl, 1,3-dioxanyl,1,4-dioxanyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,octahydrobenzofuryl, octahydrobenzothiophene, octahydrochromenyl, anddecahydroquinolinyl.

The terms “aryl” and “aromatic group” refer to an optionally substitutedmono- or polycyclic aromatic moiety in which at least one ring in themoiety is aromatic. The ring(s) in the moiety may be carbocyclic or maycontain one or more heteroatoms selected from O, S, and N. The ring(s)in the moiety may be aromatic or non-aromatic (saturated orunsaturated), but at least one ring in the moiety is aromatic. An arylor aromatic group may be monovalent (i.e., —Ar) or divalent (i.e., —Ar—)in terms of its attachment to the rest of the compound. Examples of aryland aromatic groups include, but are not limited to, phenyl, indolinyl,isoindolinyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothiophene,chromanyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, naphthyl, indenyl, and indanyl.

The terms “heteroaryl” and “heteroaromatic group” refer to an aryl oraromatic group in which at least one ring (aromatic or non-aromatic) inthe aromatic moiety contains one or more heteroatoms selected from O, S,and N. Examples of heteroaryl and heteroaromatic groups include, but arenot limited to, pyrrolyl, pyrazolyl, imidazolyl, furyl, isoxazolyl,oxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,3,5-triazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,indazolyl, benzimidazolyl, benzothiazolyl, [1,7]naphthyridinyl,chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, purinyl, pyridazinyl, quinolinyl,imidazo[4,5-c]pyridinyl, pyrido[2,3-d]pyrimidinyl,pyrimido[3,2-c]pyrimidinyl, and pyrrolo[2,3-d]pyrimidinyl.

The alkyl, aliphatic, heteroalkyl, heteroaliphatic, cycloalkyl,cycloaliphatic, heterocycloalkyl, heterocycloaliphatic, aryl, aromatic,heteroaryl and heteroaromatic groups may be substituted orunsubstituted. If substituted, they may contain from 1 to 5substituents. The substituents include, but are not limited to:optionally substituted carbon-containing groups, e.g., alkyl, cycloalkyland aryl (e.g., benzyl); halogen atoms (i.e., F, Cl, Br and I) andoptionally substituted halogen-containing groups, e.g., haloalkyl (e.g.,trifluoromethyl); optionally substituted oxygen-containing groups, e.g.,oxo, alcohols (e.g., hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), andethers (e.g., alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl); optionallysubstituted carbonyl-containing groups, e.g., aldehydes (e.g.,carboxaldehyde), ketones (e.g., alkylcarbonyl, alkylcarbonylalkyl,arylcarbonyl, arylalkylcarbonyl, arycarbonylalkyl), carboxy acids (e.g.,carboxy, carboxyalkyl), esters (e.g., alkoxycarbonyl,alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl),carbonates, thioesters, amides (e.g., aminocarbonyl, mono- ordialkylaminocarbonyl, aminocarbonylalkyl, mono- ordialkylaminocarbonylalkyl, arylaminocarbonyl, alkylarylaminocarbonyl),carbamates (e.g., alkoxycarbonylamino, arloxycarbonylamino,aminocarbonyloxy, mono- or dialkylaminocarbonyloxy,arylaminocarbonyloxy, alkylarylaminocarbonyloxy), and ureas (e.g., mono-or dialkylaminocarbonylamino, arylaminocarbonylamino,alkylarylaminocarbonylamino); optionally substituted groups containingcarbonyl derivatives, e.g., imines, oximes, and thioureas; optionallysubstituted nitrogen-containing groups, e.g., amines (e.g., amino, mono-or dialkylamino, mono- or diarylamino, alkylarylamino, aminoalkyl, mono-or dialkylaminoalkyl), azides, nitriles (e.g., cyano, cyanoalkyl) andnitro; optionally substituted sulfur-containing groups, e.g., thiols,sulfides, thioethers, sulfoxides, sulfones and sulfonamides (e.g.sulfhydryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl,arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); andoptionally substituted aromatic or non-aromatic heterocyclic groupscontaining one or more heteroatoms selected from O, S and N (e.g.,thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl,azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl,pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl,thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl,isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl,coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthyridinyl,cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl,chromenyl, chromanyl, isochromanyl, phthalazinyl, carbolinyl).

EMBODIMENTS OF THE INVENTION

Composition and Polymer

The embodiments of the present invention are designed to possess certainadvantages over conventional biodegradable polymers used to makeimplantable devices. The degradation rate of a polymer may be enhancedby the appropriate selection of monomers and ratio thereof for the“hard” and “soft” blocks of the polymer. The relatively high T_(g) orT_(m) of the “hard” blocks, above body temperature, increases thestrength and rigidity of the polymer. Further, the fracture toughness,flexibility and drug permeability of the polymer may be increased byincorporation, with the hard block polymers, of a “soft” block polymerhaving a T_(g) less than the T_(g) or T_(m) of the hard block polymers.The hard and/or soft blocks may comprise another polymer that may bemiscible or immiscible with the soft and/or hard block polymers,respectively. Finally, adhesion of a polymeric coating to a metalsurface can be promoted by appropriate (e.g., chemical) modification ofthe polymer. Such modification could lead to a single polymer, whichcould be used as a drug reservoir, with no primer.

Accordingly, one embodiment of the present invention, optionally incombination with one or more other embodiments described herein, isdirected to a composition comprising a biodegradable triblock copolymerof the structure A-B-A′, wherein:

-   -   the A and A′ blocks each independently are hard blocks having a        T_(g) or T_(m) above body temperature;    -   the B block is a soft block having a T_(g) less than the T_(g)        or T_(m) of the A and A′ blocks;    -   the A, B and A′ blocks each independently have a polymer        number-average molecular weight (M_(n)) from about 1 kDa to        about 500 kDa; and the A and A′ blocks may be the same or        different.

In one embodiment, the A and A′ blocks each independently have a T_(g)or T_(m) above body temperature when the A and A′ blocks are hydrated,and the B block has a T_(g) less than the T_(g) or T_(m) of the A and A′blocks when the B block is hydrated. In another embodiment, the A and A′blocks each independently have a T_(g) or T_(m) above body temperaturewhen the A and A′ blocks are not hydrated, and the B block has a T_(g)less than the T_(g) or T_(m) of the A and A′ blocks when the B block isnot hydrated.

The A and A′ blocks in the triblock copolymer may be the same ordifferent from one another. In an embodiment, optionally in combinationwith one or more other embodiments described herein, the A and A′ blocksare the same. In another embodiment, optionally in combination with oneor more other embodiments described herein, the A and A′ blocks aredifferent.

The B block may or may not be miscible with the A and A′ blocks. In oneembodiment, optionally in combination with one or more other embodimentsdescribed herein, the B block is partially or completely miscible withthe A and A′ blocks. In another embodiment, optionally in combinationwith one or more other embodiments described herein, the B block ispartially or completely immiscible with the A and A′ blocks.

To provide strength and rigidity, the hard A and A′ blocks areformulated so that their T_(g) or T_(m) is above body temperature. TheT_(g) or T_(m) of the A and A′ blocks can be tuned to a desired value byappropriate selection of component monomers and adjustment of theirratios and numbers. In certain embodiments, optionally in combinationwith one or more other embodiments described herein, the T_(g) or T_(m)of the A and A′ blocks independently ranges from about 35° C. to about300° C., or from about 40° C. to about 250° C., or from about 50° C. toabout 200° C., or from about 60° C. to about 150° C., or from about 70°C. to about 100° C.

High rigidity and strength may be important for implantable devicesfabricated with a polymeric material, e.g., for a stent so that thestent can support the walls of a vessel. In addition, the degradationrate of the triblock copolymers may be increased by formulating the Aand A′ blocks as polymers containing appropriate monomer(s), e.g.,poly(glycolide) (PGA) or a glycolide-containing copolymer, as furtherdescribed below.

Some conventional polymers may have a lower toughness and flexibilitythan desired, e.g., for use in stent applications. For example, certainglassy, semicrystalline polymers can have a T_(g) above human bodytemperature and tend to be brittle under physiological conditions,exhibiting low elongation. “Glassy” refers to a polymer that exhibits abrittle fracture mechanism, in which there is little or no plasticdeformation prior to failure. As a result, a stent coating fabricatedfrom such polymers can have insufficient toughness and flexibility forthe range of aggressive applications of a coated stent, such asoverlapped stents, stent through stent delivery, and bifurcations.

Some conventional polymers may also be unable to control drug release.For a polymer with low permeability of a drug, a high drug/polymer ratiomust be employed to get the drug to release. However, a highdrug/polymer ratio can lead to a drug-release profile in which most ofthe drug is released as a burst, and the remaining portion of the drugis released very slowly. On the other hand, a low drug/polymer ratio mayresult in no drug release at all.

To increase fracture toughness and flexibility and to improvedrug-release control, the B block of the inventive triblock copolymer isformulated to have a T_(g) less than the T_(g) or T_(m) of the hard Aand A′ blocks. The T_(g) of the B block can be tuned to a desired valueby appropriate selection of component monomers and adjustment of theirratios and numbers. In some embodiments, the B block has a T_(g) belowbody temperature. In further embodiments, optionally in combination withone or more other embodiments described herein, the T_(g) of the B blockranges from about −70° C. to about 150° C., or from about −50° C. toabout 100° C., or from about −25° C. to about 75° C., or from about 0°C. to about 50° C. It should be understood that in some cases, the Bblock may have a T_(m) rather than a T_(g), and the scope of the presentinvention encompasses cases where the B block has a T_(m) rather than aT_(g).

The soft block may have greater flexibility, a lower modulus, and higherfracture toughness than the hard blocks at physiological conditions. Itis believed that when a device is placed under stress, the soft blocktends to absorb energy when a fracture starts to propagate through thedevice. Crack propagation through the hard blocks may then be reduced orinhibited. As a consequence, the fracture toughness of the polymericmaterial, and thus that of the device fabricated therewith, tend to beincreased.

In one embodiment, optionally in combination with one or more otherembodiments described herein, the tensile modulus of the hard A and A′blocks independently is greater than about 1,000 MPa, and the tensilemodulus of the soft B block is less than about 1,000 MPa. In a narrowerembodiment, the tensile modulus of the hard A and A′ blocksindependently is greater than about 1,500 MPa, and the tensile modulusof the soft B block is less than about 750 MPa. In a still narrowerembodiment, the tensile modulus of the hard A and A′ blocksindependently is greater than about 2,000 MPa, and the tensile modulusof the soft B block is less than about 500 MPa.

The soft B block of the triblock copolymer may be composed of a rubberyor elastomeric polymer. An “elastomeric” or “rubbery” polymer refers toa polymer that exhibits elastic deformation through all or most of arange of deformation. The soft B block may also be substantially orcompletely amorphous. For example, the B block can have a degree ofcrystallinity of about 10% or less.

Examples of biodegradable polymers having a relatively high fracturetoughness at body temperature include, but are not limited to,polycaprolactone (PCL), poly(trimethylene carbonate) (PTMC),polydioxanone, poly(propiolactone), poly(valerolactone) and polyacetal.Accordingly, some embodiments of the soft B block of the triblockcopolymer can include caprolactone (CL), trimethylene carbonate (TMC),dioxanone, propiolactone, valerolactone or acetal monomer units, or acombination thereof.

Within the polymer chain, the hard blocks are anchored to the soft blockthrough covalent bonds. In systems where the A, A′ and B blocks havesome degree of immiscibility, different domains, rich in soft blocks orhard blocks, form within the bulk polymer. These domains are bound toeach other via the polymer chains they share. Hence, there is goodadhesion between the hard and soft blocks. The high degree of adhesionprovided by the covalent bonding facilitates energy transfer between thehard and soft blocks, and thus increases the fracture toughness of thetriblock copolymer. It is believed that without the anchoring oradhesion provided by the covalent bonding, a propagating crack may goaround the soft block, reducing the effectiveness of the soft block inabsorbing energy imparted to a device.

When the hard and soft blocks phase-separate, various morphologies maybe formed. The specific morphology formed depends on the relativeamounts of the hard and soft blocks, as well as their chemical nature.In general, when the soft block comprises a small volume fraction of thepolymer, it tends to exist as a dispersed phase in a continuous phase ofthe hard block(s). When the hard block comprises a small volumefraction, it tends to exist as a dispersed phase in a continuous phaseof soft block. Variations of the ratio of soft to hard blocks allow oneto tune/modify the properties of the polymeric material, e.g., the drugpermeability and drug-release rate of the material.

The degradation rate of the triblock copolymers can be influenced by thephysical state of the hard and soft blocks. Since the diffusion rate offluids through an amorphous structure is generally faster than through acrystalline structure, the hard blocks and/or soft block may exhibit ahigher degree of amorphousness to increase the degradation rate. Thefaster degrading hard blocks and/or soft block increase waterpenetration and content in those blocks. The increased water penetrationand content causes an increase in the degradation rate of the polymericmaterial and thus the device.

The degradation rate of the triblock copolymers can also be influencedby the identity of the monomer units making up the hard and soft blocks.For example, the hard blocks and/or soft block may include units thatare hydrophilic and/or hydrolytically active. These two characteristicsincrease the moisture content of the polymeric material, which increasesthe degradation rate of the polymer. Additionally, the hard blocksand/or soft block may also contain units that have acidic or hydrophilicdegradation products. Since the rate of the hydrolysis reaction tends toincrease as the pH decreases, acidic degradation products can increasethe degradation rate of the polymeric material and hence the device.

As an illustrative example, faster degrading polymers may contain theglycolide (GA) monomer. When incorporated into a polymer, glycolic acidhydrolyzes faster than L-lactic acid or D-lactic acid, for the esterbond formed from glycolic acid is less sterically hindered than thatformed from lactic acid. Further, glycolide units have acidicdegradation products that can increase the degradation rate of aglycolide-containing polymeric material. Moreover, glycolic acid is alow molecular weight monomer, so that an appreciable level of glycolicacid means that there is a substantial number of ester bonds formed fromglycolic acid in a glycolide-containing polymer, any or all of which canhydrolyze. For example, a fast degrading polymer ispoly(glycolide-co-trimethylene carbonate) (P(GA-co-TMC)).

In some embodiments, the soft B block can include toughness-enhancingunits and fast degrading units. In more specific embodiments, the softblock may include GA, CL, TMC, valerolactone, propiolactone or acetalunits, or a combination thereof. The B block can have alternating orrandom GA, CL, TMC, valerolactone, propiolactone and acetal units. Forexample, the B block can be poly(GA-co-CL), poly(GA-co-TMC), orpoly(GA-co-TMC-co-CL).

The flexibility, toughness and degradation rate of the soft B block canalso be adjusted by the ratio of fast degrading and toughness-enhancingunits. For example, as the ratio of CL increases in poly(GA-co-CL), theblock copolymer becomes more flexible and tougher.

Further, the degradation rate of the B block, and hence that of thepolymeric material, can be increased by increasing the fraction of GA inthe B block. In exemplary embodiments, the poly(GA-co-CL) orpoly(GA-co-TMC) segments can have greater than 1 wt %, 5 wt %, 20 wt %,50 wt %, 70 wt % or 80 wt % GA units.

The mechanical properties (e.g., rigidity, strength, toughness andflexibility), degradation rate and drug permeability of the inventivetriblock copolymer can be tuned by appropriate selection of the monomerunits of the hard and soft blocks, the ratio of the monomers within theblocks, the length or molecular weight of the blocks, the weight ratioof the blocks, and any other substances chemically or non-chemicallyincorporated with the triblock copolymer.

For forming films, the entire polymer needs to have sufficient molecularweight. Accordingly, in some embodiments, optionally in combination withone or more other embodiments described herein, the triblock copolymershave a polymer number-average molecular weight (M_(n)) of at least about20 kDa. In other embodiments, the triblock copolymers have an M_(n) ofat least about 40 kDa.

In an embodiment, optionally in combination with one or more otherembodiments described herein, the triblock copolymers range in M_(n)from about 20 kDa to about 1,000 kDa. In another embodiment, thetriblock copolymers range in M_(n) from about 20 kDa to about 500 kDa. Apolymer with an M_(n) from about 20 kDa to about 500 kDa may be moreamenable to being processed into a coating. In yet another embodiment,the triblock copolymers range in M_(n) from about 40 kDa to about 500kDa.

For the blocks to form discrete phases which are indicative of animmiscible system, they need to be of a certain minimal size. When atwo-phase system forms, each phase is saturated with the other phase,although these saturated concentrations may be very small. Accordingly,in some embodiments, the A, A′ and B blocks each independently have anM_(n) of at least about 1 kDa. In certain embodiments, optionally incombination with one or more other embodiments described herein, the A,A′ and B blocks each independently range in M_(n) from about 1 kDa toabout 500 kDa, or from about 10 kDa to about 400 kDa, or from about 20kDa to about 300 kDa, or from about 30 kDa to about 200 kDa, or fromabout 40 kDa to about 100 kDa.

In further embodiments, optionally in combination with one or more otherembodiments described herein, the ratio of the molecular weight of eachof the A and A′ blocks to the B block is between about 20:1 and about1:20, more narrowly between about 10:1 and about 1:10, and still morenarrowly between about 5:1 and about 1:5.

In other embodiments, optionally in combination with one or more otherembodiments described herein, the weight fraction of the A and A′ blockswith respect to the total triblock copolymer is from about 1% to about99%, more narrowly from about 10% to about 90%, still more narrowly fromabout 20% to about 80%, even more narrowly from about 30% to about 70%,and still even more narrowly from about 40% to about 60%. In yet otherembodiments, the triblock copolymer can contain about 1-30 wt %, or morenarrowly about 2-20 wt %, of the B block and about 70-99% wt %, or 80-98wt %, of the A and A′ blocks.

In yet other embodiments, optionally in combination with one or moreother embodiments described herein, the A, B and A′ blocks eachindependently comprise a polymer comprising from one to four differenttypes of monomer, wherein each type of monomer has from about 5 to about5,000 monomer units. In narrower embodiments, each type of monomer inthe polymer of the A, B or A′ block independently has from about 10 toabout 4,500 monomer units, or from about 20 to about 4,000 monomerunits, or from about 30 to about 3,500 monomer units, or from about 40to about 3,000 monomer units, or from about 50 to about 2,500 monomerunits.

According to further embodiments of the present invention, optionally incombination with one or more other embodiments described herein:

-   -   the A and A′ blocks each independently comprise a polymer        selected from the group consisting of poly(L-lactide) (PLLA),        poly(D,L-lactide), poly(glycolide) (PGA),        poly(GA-co-D,L-lactide), poly(GA-co-L-lactide), and any        variations in the arrangement of the monomers thereof, and    -   the B block comprises a polymer selected from the group        consisting of poly(caprolactone) (PCL), poly(CL-co-GA),        poly(trimethylene carbonate) (PTMC), poly(TMC-co-GA),        poly(TMC-co-D,L-lactide), poly(TMC-co-L-lactide),        poly(TMC-co-CL), poly(TMC-co-D,L-lactide-co-GA),        poly(TMC-co-CL-co-GA), poly(dioxanone), poly(TMC-co-dioxanone),        poly(dioxanone-co-CL), poly(dioxanone-co-D,L-lactide),        poly(dioxanone-co-L-lactide), poly(dioxanone-co-GA),        poly(dioxanone-co-D,L-lactide-co-GA), polyketals, and any        variations in the arrangement of the monomers thereof.

In some embodiments, optionally in combination with one or more otherembodiments described herein, the A, A′ and B blocks specifically cannotcomprise one or more of any of the aforementioned polymers.

The A and A′ blocks can comprise PGA or a glycolide-containing copolymerto achieve fast degradation. To provide strength and rigidity, the hardA and A′ blocks are formulated so that their T_(g) or T_(m) is abovebody temperature. In some embodiments, if the A and/or the A′ blockscomprise poly(L-lactide) or poly(D,L-lactide), then the B blockcomprises a glycolide-containing polymer.

To increase fracture toughness, flexibility and drug permeability, the Bblock is formulated to have a T_(g) less than the T_(g) or T_(m) of theA and A′ blocks. In some embodiments, the B block has a T_(g) below bodytemperature. For example, poly(TMC) has a T_(g) of −15° C., andpoly(dioxanone) has a T_(g) of −10° C. to 0° C. The B block may beformulated to be miscible or immiscible with the A and A′ blocks. Insome embodiments, the B block is immiscible with the A and A′ blocks.

In an embodiment, optionally in combination with one or more otherembodiments described herein, the polyketal polymer of the B block hasthe structure of

According to one embodiment, optionally in combination with one or moreother embodiments described herein, R₁ is a poly(caprolactone) diol or aC₂-C₂₄ diol of the structure, HO—R₁—OH, that contains an optionallysubstituted aliphatic, heteroaliphatic, cycloaliphatic,heterocycloaliphatic, aromatic or heteroaromatic group, or a combinationthereof, and n is an integer from about 5 to about 5,000.

In narrower embodiments, n for the polyketal polymer is an integer fromabout 10 to about 4,500, or from about 20 to about 4,000, or from about30 to about 3,500, or from about 40 to about 3,000, or from about 50 toabout 2,500.

In an embodiment, optionally in combination with one or more otherembodiments described herein, the polyketal polymer has a polymernumber-average molecular weight (M_(n)) from about 0.5 kDa to about 500kDa. In narrower embodiments, the polyketal polymer has an M_(n) in therange from about 1 kDa to about 500 kDa, or from about 10 kDa to about400 kDa, or from about 20 kDa to about 300 kDa, or from about 30 kDa toabout 200 kDa, or from about 40 kDa to about 100 kDa.

In a further embodiment, R₁ is a poly(caprolactone) diol. In otherembodiments, R₁ is a C₂-C₂₄ diol, more narrowly a C₂-C₁₆ diol, or evenmore narrowly a C₂-C₈ diol.

One of ordinary skill in the art would understand the structural natureof R₁ in light of the definition of “aliphatic”, “heteroaliphatic”,“cycloaliphatic”, “heterocycloaliphatic”, “aromatic” and“heteroaromatic” provided earlier. In some embodiments, optionally incombination with one or more other embodiments described herein, the R₁diol specifically cannot be any particular one of the various diols thatfall within the genus of the R₁ diol, as defined herein. In a particularembodiment, the R₁ diol specifically cannot be a poly(caprolactone)diol.

The polyketal polymer of the B block possesses properties that make it asuitable component of the inventive biodegradable triblock copolymer.The ketal linkages in the backbone of the polyketal polymer undergorapid acid-catalyzed hydrolysis. The degradation products, C₂-C₂₄HO—R₁—OH and acetone, are low molecular weight, excretable compoundsthat in many cases are water-soluble and not acidic. Thus, the polyketalpolymer is an acid-sensitive, biodegradable polymer that is expected torelease an incorporated drug at an accelerated rate in acidicenvironments. The polyketal polymer may degrade faster than somepolymers (e.g., PLGA), but more slowly than other polymers (e.g.,poly(ortho esters) and poly(β-amino esters)), thereby permitting thetuning of drug-release rates to a particular application.

Selection of a different R₁ group gives a polyketal polymer having adifferent T_(g), and thus allows for the tuning of the flexibility andtoughness of the polymer. Further, selection of different R₁ groupsdiffering in their degree of lipophilicity and steric bulkiness yieldspolyketal polymers differing in hydrophobicity/hydrophilicity and sterichindrance around the ketal linkages. This would affect the degradationrate and the drug-release rate of the triblock copolymer containing thepolyketal polymer.

Poly(caprolactone) can be a flexible polymer having a T_(g) of about−60° C. (the T_(g)/T_(m) of PCL is tunable depending on, e.g., itsmolecular weight). PCL may also be tuned to degrade more slowly, e.g.,in about 1-2 years. Therefore, the use of poly(caprolactone) diol as theR₁ diol can result in a polyketal that is softer and more flexible, butdegrades more slowly, than polyketals based on an aromatic R₁ diol(e.g., 1,4-benzenedimethanol).

The polyketal polymer may be synthesized by any of various methods knownin the art. For example, the polyketal polymer may be synthesized byacid-catalyzed polycondensation of the diol, HO—R₁—OH, with an acetonesource such as acetone or 2,2-dimethoxypropane. The synthesis may bedone in the presence of excess diol, which would result in ahydroxyl-terminated polymer segment that may be used to initiate growthof other segments of the B block or growth of the A and A′ blocks byring-opening polymerization.

Advantages of the A-B-A′ triblock copolymers of the present invention(e.g., poly(GA-ran-LLA)-block-poly(TMC)-block-poly(GA-ran-LLA)) overconventional biodegradable polymers include, but are not limited to:

-   -   The degradation rates of the inventive triblock copolymers        (e.g., glycolide-containing polymers) can be tunable such that        the polymers completely or substantially completely degrade over        a desired period of time (e.g., one year or less).    -   The triblock structure can permit a degree of tuning of the        mechanical properties (e.g., strength, rigidity, toughness,        flexibility and elongation) of the triblock polymers by        selection of the appropriate monomer components of the A, B and        A′ blocks and by variation of the molecular weights of the        blocks and the relative ratios of the monomers within the        blocks.    -   Because the soft B block has a T_(g) less than the T_(g) or        T_(m) of the A and A′ blocks, it can provide a higher        permeability to drugs than the A and A′ blocks. Therefore, the        triblock copolymers of the invention can have a higher drug        permeability than polymers formed of the A and A′ blocks only,        e.g., pure poly(D,L-lactide-co-glycolide) (PLGA). The higher        drug permeability can allow better control of drug-release rates        at reasonable drug-to-polymer ratios, e.g., where the amount of        polymer is greater than 50% by weight.

An additional advantage of the inventive triblock copolymers is theircompatibility with terminal sterilization techniques. Various terminalsterilization processes are available for sterilizing implantabledevices such as drug-delivery stents. Many of these processes, such aselectron beam and gamma irradiation, can cause degradation of the drug.Ethylene oxide gas (EOG) tends to cause less drug degradation. DuringEOG sterilization, however, the drug-delivery coating is exposed to acombination of heat, humidity and EOG. With many conventionalbiodegradable polymers, such a combination of conditions softens thecoating, leading to coating flow and deformation. Unlike somebiodegradable polymeric coatings, the triblock copolymers of theinvention are compatible with EOG sterilization.

Some polymers also cannot adhere to metal surfaces. For a polymer thatdoes not have any inherent adhesion to metal surfaces, a primer of thatpure polymer may have to be used to achieve optimum adhesion to metalstents.

The triblock copolymers of the invention have characteristics thatimprove their adhesion to metal surfaces. For example, the B block witha lower T_(g) is expected to interact favorably with a metal substrateat body temperature. Moreover, the different polarity of the hard A andA′ blocks and the soft B block increases the chance of favorablenon-covalent adhesive interactions with metal substrates.

To improve adhesion of the triblock copolymers to metal surfaces, atleast one dihydroxyaryl group could be conjugated to the polymer ends ofthe triblock copolymers. The dihydroxyaryl group(s) may contain adihydroxyphenyl moiety. Ortho-dihydroxyphenyl groups in3,4-dihydroxyphenyl alanine have been shown to be responsible for thebonding of mussel adhesive proteins to a variety of metallic substrates.B. P. Lee et al., Biomacromolecules, 3: 1038-1047 (2002). Other3,4-dihydroxyphenyl-containing compounds that may be conjugated to thepolymer ends of the triblock copolymers to increase their adhesion tometal surfaces include, e.g., dopamine and 3,4-dihydroxyhydrocinnamicacid.

Accordingly, in some embodiments, optionally in combination with one ormore other embodiments described herein, at least one dihydroxyarylgroup is conjugated to the polymer ends of the triblock copolymer. In anembodiment, the at least one dihydroxyaryl group contains anortho-dihydroxyphenyl moiety. In one embodiment, the at least onedihydroxyaryl group contains a 1,2-dihydroxyphenyl moiety. In anotherembodiment, the at least one dihydroxyaryl group contains a3,4-dihydroxyphenyl moiety. 3,4-Dihydroxyphenyl-containing compoundsthat could be conjugated to the polymer ends of a triblock copolymerinclude, e.g., dopamine and 3,4-dihydroxyhydrocinnamic acid.

Biocompatible Moieties

Another embodiment of the invention, optionally in combination with oneor more other embodiments described herein, is drawn to a compositioncomprising an A-B-A′ triblock copolymer of the invention and at leastone biologically compatible (or “biocompatible”) moiety. The at leastone biocompatible moiety may be blended or bonded with the triblockcopolymer. If bonded with the triblock copolymer, the biocompatiblemoiety may be included in the A, B and/or A′ bocks, providing the ABA′triblock copolymer with biological, e.g., blood, compatibility. Thebiocompatible moieties may be selected in such a way as to make theentire ABA′ triblock copolymer biologically degradable.

Examples of suitable biocompatible moieties include, but are not limitedto, poly(alkylene glycols), e.g., poly(ethylene glycol) (PEG),poly(ethylene oxide), poly(propylene glycol) (PPG), poly(tetramethyleneglycol) and poly(ethylene oxide-co-propylene oxide); lactones andlactides, e.g., ε-caprolactone, β-butyrolactone, δ-valerolactone andglycolide; poly(N-vinyl pyrrolidone); poly(acrylamide methyl propanesulfonic acid) and salts thereof (AMPS and salts thereof); poly(styrenesulfonate); sulfonated dextran; polyphosphazenes; poly(orthoesters);poly(tyrosine carbonate); sialic acid; hyaluronic acid; hyaluronic acidhaving a stearoyl or palmitoyl substitutent group; copolymers of PEGwith hyaluronic acid, hyaluronic acid-stearoyl or hyaluronicacid-palmitoyl; heparin; copolymers of PEG with heparin; a graftcopolymer of poly(L-lysine) and PEG; or copolymers thereof. Themolecular weight of a biocompatible polymeric moiety may be below 40 kDato ensure renal clearance of the compound, e.g., between about 300 andabout 40,000 Daltons, or between about 8,000 and about 30,000 Daltons,e.g., about 15,000 Daltons.

Accordingly, in one embodiment, the at least one biocompatible moiety isselected from the group consisting of poly(ethylene oxide),poly(propylene glycol), poly(tetramethylene glycol), polyethyleneoxide-co-propylene oxide), ε-caprolactone, β-butyrolactone,δ-valerolactone, glycolide, poly(N-vinyl pyrrolidone), poly(acrylamidemethyl propane sulfonic acid) and salts thereof, poly(styrenesulfonate), sulfonated dextran, polyphosphazenes, poly(orthoesters),poly(tyrosine carbonate), sialic acid, hyaluronic acid or derivativesthereof, copolymers of poly(ethylene glycol) with hyaluronic acid orderivatives thereof, heparin, copolymers of polyethylene glycol withheparin, a graft copolymer of poly(L-lysine) and poly(ethylene glycol),and copolymers thereof.

In some embodiments, optionally in combination with one or more otherembodiments described herein, the at least one biocompatible moietyspecifically cannot be one or more of any of the biocompatible moietiesdescribed herein.

Biologically Absorbable Polymers

Yet another embodiment of the invention, optionally in combination withone or more other embodiments described herein, is directed to acomposition comprising an A-B-A′ triblock copolymer of the invention andat least one additional biologically absorbable polymer. The at leastone additional bioabsorbable polymer may impart desired properties tothe composition. Such a polymer may be blended or bonded with thetriblock copolymer.

Examples of biologically absorbable polymers include, but are notlimited to:

-   -   (1) poly(hydroxybutyrate) (PHB);    -   (2) poly(hydroxyvalerate) (PHV);    -   (3) poly(hydroxybutyrate-co-valerate) (PHB-HV);    -   (4) poly(caprolactone) (PCL);    -   (5) poly(lactide-co-glycolide) (PLGA);    -   (6) ABA triblock copolymers of PEG with poly(butylene        terephthalate) (PBT), e.g.,        poly(ethylene-glycol)-block-poly(butyleneterephthalate)        (PEG-PBT), poly(ethylene-glycol)-block-poly (butylene        terephthalate)-block-poly(ethylene-glycol) (PEG-PBT-PEG), and        poly(butyleneterephthalate)-block-poly(ethylene-glycol)-block        poly(butyleneterephthalate) (PBT-PEG-PBT); and    -   (7) ABA triblock copolymers of PEG with PCL, e.g.,        poly(ethylene-glycol)-block-poly(caprolactone) (PEG-PCL),        poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol)        (PEG-PCL-PEG), and        poly(caprolactone)-block-poly(ethylene-glycol)-block-poly(caprolactone)        (PCL-PEG-PCL).

Any combination of bioabsorable polymers of groups (1)-(7) above mayalso be used. PEG-PBT and PEG-PBT-PEG block copolymers are known underthe trade name POLYACTIVE™ and are available from IsoTis Corp. ofHolland. These polymers can be obtained, e.g., by trans-esterificationof dibutyleneterephthalate with PEG. In POLYACTIVE™, the ratio betweenthe units derived from ethylene glycol and the units derived frombutylene terephthalate can be between about 0.67:1 and about 9:1. Themolecular weight of the units derived from ethylene glycol can bebetween about 300 and about 4,000 Daltons, and the molecular weight ofthe units derived from butylene terephthalate can be between about50,000 and about 250,000, e.g., about 100,000 Daltons.

DLPLA-PEG-DLPLA, PEG-DLPLA-PEG, PEG-PBT, PEG-PBT-PEG, PBT-PEG-PBT,PEG-PCL, PEG-PCL-PEG, and PCL-PEG-PCL block copolymers all containfragments with ester bonds. Ester bonds are known to be water-labilebonds. When in contact with slightly alkaline blood, ester bonds aresubject to base-catalyzed hydrolysis, thus ensuring biologicaldegradability of the block copolymers. One product of degradation ofevery block polymer belonging to the group of DLPLA-PEG-DLPLA,PEG-DLPLA-PEG, PEG-PBT, PEG-PBT-PEG, PBT-PEG-PBT, PEG-PCL, PEG-PCL-PEG,and PCL-PEG-PCL is expected to be PEG, which is highly biologicallycompatible.

Accordingly, in an embodiment, the at least one additional biologicallyabsorbable polymer is selected from the group consisting ofpoly(hydroxybutyrate), poly(hydroxyvalerate),poly(hydroxybutyrate-co-valerate), poly(caprolactone),poly(lactide-co-glycolide),poly(ethylene-glycol)-block-poly(butyleneterephthalate),poly(ethylene-glycol)-block-poly(butyleneterephthalate)-block-polyethylene-glycol),poly(butyleneterephthalate)-block-poly(ethylene-glycol)-blockpoly(butyleneterephthalate),poly(ethylene-glycol)-block-poly(caprolactone),poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol),poly(caprolactone)-block-poly(ethylene-glycol)-block-poly(caprolactone),and blends thereof.

In some embodiments, optionally in combination with one or more otherembodiments described herein, the at least one additional biologicallyabsorbable polymer specifically cannot be one or more of any of thebioabsorbable polymers described herein.

Biologically Active Agents

A further embodiment of the invention, optionally in combination withone or more other embodiments described herein, is directed to acomposition comprising an A-B-A′ triblock copolymer of the invention andat least one biologically active (or “bioactive”) agent. The at leastone biologically active agent may include any substance capable ofexerting a therapeutic, prophylactic or diagnostic effect for a patient.

Examples of suitable bioactive agents include, but are not limited to,synthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic or diagnostic activities.Nucleic acid sequences include genes, antisense molecules that bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of other bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy. The bioactive agents couldbe designed, e.g., to inhibit the activity of vascular smooth musclecells. They could be directed at inhibiting abnormal or inappropriatemigration and/or proliferation of smooth muscle cells to inhibitrestenosis.

In an embodiment, the inventive composition comprises at least onebiologically active agent selected from the group consisting ofantiproliferative, antineoplastic, antimitotic, anti-inflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,antiallergic and antioxidant substances.

An antiproliferative agent can be a natural proteineous agent such as acytotoxin or a synthetic molecule. Examples of antiproliferativesubstances include, but are not limited to, actinomycin D or derivativesand analogs thereof (manufactured by Sigma-Aldrich, or COSMEGENavailable from Merck) (synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin I₁, actinomycin X₁, and actinomycin C₁); alltaxoids such as taxols, docetaxel, and paclitaxel and derivativesthereof, all olimus drugs such as macrolide antibiotics, rapamycin,everolimus, structural derivatives and functional analogues ofrapamycin, structural derivatives and functional analogues ofeverolimus, FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone,prodrugs thereof, co-drugs thereof, and combinations thereof. Examplesof rapamycin derivatives include, but are not limited to,40-O-(2-hydroxy)ethyl-rapamycin (trade name everolimus from Novartis),40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus, manufactured by AbbottLabs.), prodrugs thereof, co-drugs thereof, and combinations thereof.

An anti-inflammatory drug can be a steroidal anti-inflammatory drug, anonsteroidal anti-inflammatory drug (NSAID), or a combination thereof.Examples of anti-inflammatory drugs include, but are not limited to,alclofenac, alclometasone dipropionate, algestone acetonide, alphaamylase, amcinafal, amcinafide, amfenac sodium, amiprilosehydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazidedisodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol, clobetasol propionate, clobetasone butyrate, clopirac,cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort,desonide, desoximetasone, dexamethasone, dexamethasone acetate,dexamethasone dipropionate, diclofenac potassium, diclofenac sodium,diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate,diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab,enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole,fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac,flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate,flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugsthereof, and combinations thereof.

Alternatively, the anti-inflammatory agent may be a biological inhibitorof pro-inflammatory signaling molecules. Anti-inflammatory biologicalagents include antibodies to such biological inflammatory signalingmolecules.

In addition, the bioactive agents can be other than antiproliferative oranti-inflammatory agents. The bioactive agents can be any agent that isa therapeutic, prophylactic or diagnostic agent. In some embodiments,such agents may be used in combination with antiproliferative oranti-inflammatory agents. These bioactive agents can also haveantiproliferative and/or anti-inflammmatory properties or can have otherproperties such as antineoplastic, antimitotic, cystostatic,antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,antiallergic, and/or antioxidant properties.

Examples of antineoplastics and/or antimitotics include, but are notlimited to, paclitaxel (e.g., TAXOL® available from Bristol-MyersSquibb), docetaxel (e.g., Taxotere® from Aventis), methotrexate,azathioprine, vincristine, vinblastine, fluorouracil, doxorubicinhydrochloride (e.g., Adriamycin® from Pfizer), and mitomycin (e.g.,Mutamycin® from Bristol-Myers Squibb).

Examples of antiplatelet, anticoagulant, antifibrin, and antithrombinagents that may also have cytostatic or antiproliferative propertiesinclude, but are not limited to, sodium heparin, low molecular weightheparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, thrombin inhibitors such as ANGIOMAX (from Biogen),calcium channel blockers (e.g., nifedipine), colchicine, fibroblastgrowth factor (FGF) antagonists, fish oil (e.g., omega 3-fatty acid),histamine antagonists, lovastatin (a cholesterol-lowering drug thatinhibits HMG-CoA reductase, brand name Mevacor® from Merck), monoclonalantibodies (e.g., those specific for platelet-derived growth factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), nitricoxide or nitric oxide donors, super oxide dismutases, super oxidedismutase mimetics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), estradiol, anticancer agents, dietary supplements suchas various vitamins, and a combination thereof.

Examples of cytostatic substances include, but are not limited to,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g., Capoten® and Capozide® from Bristol-Myers Squibb), cilazapril andlisinopril (e.g., Prinivil® and Prinzide® from Merck).

Examples of antiallergic agents include, but are not limited to,permirolast potassium. Examples of antioxidant substances include, butare not limited to, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO).

Other bioactive agents may include anti-infectives such as antiviralagents; analgesics and analgesic combinations; anorexics;antihelmintics; antiarthritics, antiasthmatic agents; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihistamines;antimigrain preparations; antinauseants; antiparkinsonism drugs;antipruritics; antipsychotics; antipyretics; antispasmodics;anticholinergics; sympathomimetics; xanthine derivatives; cardiovascularpreparations including calcium channel blockers and beta-blockers suchas pindolol and antiarrhythmics; antihypertensives; diuretics;vasodilators including general coronary vasodilators; peripheral andcerebral vasodilators; central nervous system stimulants; cough and coldpreparations, including decongestants; hypnotics; immunosuppressives;muscle relaxants; parasympatholytics; psychostimulants; sedatives;tranquilizers; naturally derived or genetically engineered lipoproteins;and restenoic reducing agents.

Other biologically active agents that may be used includealpha-interferon, genetically engineered epithelial cells, tacrolimusand dexamethasone.

A “prohealing” drug or agent, in the context of a blood-contactingimplantable device, refers to a drug or agent that has the property thatit promotes or enhances re-endothelialization of arterial lumen topromote healing of the vascular tissue. The portion(s) of an implantabledevice (e.g., a stent) containing a prohealing drug or agent canattract, bind and eventually become encapsulated by endothelial cells(e.g., endothelial progenitor cells). The attraction, binding, andencapsulation of the cells will reduce or prevent the formation ofemboli or thrombi due to the loss of the mechanical properties thatcould occur if the stent was insufficiently encapsulated. The enhancedre-endothelialization may promote the endothelialization at a ratefaster than the loss of mechanical properties of the stent.

The prohealing drug or agent can be dispersed in the body of thebioabsorbable polymer substrate or scaffolding. The prohealing drug oragent can also be dispersed within a bioabsorbable polymer coating overa surface of an implantable device (e.g., a stent).

“Endothelial progenitor cells” refer to primitive cells made in the bonemarrow that can enter the bloodstream and go to areas of blood vesselinjury to help repair the damage. Endothelial progenitor cells circulatein adult human peripheral blood and are mobilized from bone marrow bycytokines, growth factors, and ischemic conditions. Vascular injury isrepaired by both angiogenesis and vasculogenesis mechanisms. Circulatingendothelial progenitor cells contribute to repair of injured bloodvessels mainly via a vasculogenesis mechanism.

In some embodiments, the prohealing drug or agent can be an endothelialcell (EDC)-binding agent. In certain embodiments, the EDC-binding agentcan be a protein, peptide or antibody, which can be, e.g., one ofcollagen type 1, a 23 peptide fragment known as single chain Fv fragment(scFv A5), a junction membrane protein vascular endothelial(VE)-cadherin, and combinations thereof. Collagen type 1, when bound toosteopontin, has been shown to promote adhesion of endothelial cells andmodulate their viability by the down regulation of apoptotic pathways.S. M. Martin, et al., J. Biomed. Mater. Res., 70A:10-19 (2004).Endothelial cells can be selectively targeted (for the targeted deliveryof immunoliposomes) using scFv A5. T. Volkel, et al., Biochimica etBiophysica Acta, 1663:158-166 (2004). Junction membrane protein vascularendothelial (VE)-cadherin has been shown to bind to endothelial cellsand down regulate apoptosis of the endothelial cells. R. Spagnuolo, etal., Blood, 103:3005-3012 (2004).

In some embodiments, the EDC-binding agent can be the active fragment ofosteopontin, (Asp-Val-Asp-Val-Pro-Asp-Gly-Asp-Ser-Leu-Ala-Try-Gly).Other EDC-binding agents include, but are not limited to, EPC(epithelial cell) antibodies, RGD peptide sequences, RGD mimetics, andcombinations thereof.

In further embodiments, the prohealing drug or agent may be a substanceor agent that attracts and binds endothelial progenitor cells.Representative substances or agents that attract and bind endothelialprogenitor cells include antibodies such as CD-34, CD-133 and vegf type2 receptor. An agent that attracts and binds endothelial progenitorcells can include a polymer having nitric oxide donor groups.

The foregoing biologically active agents are listed by way of exampleand are not meant to be limiting. Other biologically active agents thatare currently available or that may be developed in the future areequally applicable.

In a more specific embodiment, optionally in combination with one ormore other embodiments described herein, the composition of theinvention comprises at least one biologically active agent selected fromthe group consisting of paclitaxel, docetaxel, estradiol, nitric oxidedonors, super oxide dismutases, super oxide dismutase mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-raparnycin,40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, progenitor cell-capturing antibodies,prohealing drugs, prodrugs thereof, co-drugs thereof, and a combinationthereof. In a particular embodiment, the bioactive agent is everolimus.In another specific embodiment, the bioactive agent is clobetasol.

In some embodiments, optionally in combination with one or more otherembodiments described herein, the at least one biologically active agentspecifically cannot be one or more of any of the bioactive drugs oragents described herein.

Material and Coating

The inventive composition comprising a biodegradable ABA′ triblockcopolymer may be used to make a material of which an implantable deviceis formed. Such a material may comprise any combination of embodimentsof the inventive composition described herein.

Accordingly, an embodiment of the invention, optionally in combinationwith one or more other embodiments described herein, is drawn to amaterial containing any combination of embodiments of the compositioncomprising a biodegradable ABA′ triblock copolymer. For example, thecomposition forming the material may optionally have at least onedihydroxyaryl group conjugated to the polymer ends of the triblockcopolymer and optionally contain at least one biocompatible moiety, atleast one additional biologically absorbable polymer, and/or at leastone biologically active agent.

The material of the invention may be used to make a portion of animplantable device or the whole device itself. Moreover, the materialmay be used to make a coating that is disposed over at least a portionof an implantable device.

Accordingly, a embodiment of the invention, optionally in combinationwith one or more other embodiments described herein, is directed to acoating containing any combination of embodiments of the compositioncomprising a biodegradable ABA′ triblock copolymer. For example, thecomposition forming the coating may optionally have at least onedihydroxyaryl group conjugated to the polymer ends of the triblockcopolymer and optionally contain at least one biocompatible moiety, atleast one additional biologically absorbable polymer, and/or at leastone biologically active agent.

The coating may have a variety of thickness and biodegradation rates. Insome embodiments, optionally in combination with one or more otherembodiments described herein, the coating has a thickness of ≦bout 30micron, or ≦about 20 micron, or ≦about 10 micron. In furtherembodiments, optionally in combination with one or more otherembodiments described herein, the biodegradation rate of the coating ischaracterized by loss of about 100% mass within about two years, or lossof about 100% mass within about 12 months, or loss of at least about 70%mass within about six months.

Implantable Device

The inventive material containing any combination of embodiments of thecomposition comprising a biodegradable ABA′ copolymer may be used toform an implantable device. Accordingly, one embodiment of theinvention, optionally in combination with one or more other embodimentsdescribed herein, is drawn to an implantable device formed of a materialcontaining any combination of embodiments of the composition comprisinga biodegradable ABA′ copolymer. For example, the implantable device maybe formed of a material comprising a composition that optionally has atleast one dihydroxyaryl group conjugated to the polymer ends of thetriblock copolymer and optionally contains at least one biocompatiblemoiety, at least one additional biologically absorbable polymer, and/orat least one biologically active agent.

A portion of the implantable device or the whole device itself may beformed of the material containing any combination of embodiments of thecomposition comprising a biodegradable ABA′ copolymer. Further, at leasta portion of the implantable device may be coated by a coatingcontaining any combination of embodiments of the composition comprisinga biodegradable ABA′ copolymer.

Accordingly, an embodiment of the invention, optionally in combinationwith one or more other embodiments described herein, is directed to animplantable device formed of a coating containing any combination ofembodiments of the composition comprising a biodegradable ABA′copolymer. For example, the implantable device may be formed of acoating comprising a composition that optionally has at least onedihydroxyaryl group conjugated to the polymer ends of the triblockcopolymer and optionally contains at least one biocompatible moiety, atleast one additional biologically absorbable polymer, and/or at leastone biologically active agent.

The implantable device may be formed of a coating that may have avariety of thickness and biodegradation rates. In some embodiments,optionally in combination with one or more other embodiments describedherein, the implantable device is formed of a coating that has athickness of ≦about 30 micron, or ≦about 20 micron, or ≦about 10 micron.In further embodiments, optionally in combination with one or more otherembodiments described herein, the implantable device is formed of acoating whose biodegradation rate is characterized by loss of about 100%mass within about two years, or loss of about 100% mass within about 12months, or loss of at least about 70% mass within about six months.

The present invention also encompasses implantable devices formed ofbioabsorbable and/or biostable polymers. In some embodiments, optionallyin combination with one or more other embodiments described herein, aportion of the device or the whole device itself can be formed of suchpolymers and any other substances described herein.

Any implantable device can be formed of the inventive material orcoating. Examples of implantable devices include, but are not limitedto, stents (e.g., coronary stents and peripheral stents), grafts (e.g.,aortic grafts, arterio-venous grafts and by-pass grafts), stent-grafts,catheters, leads and electrodes for pacemakers and defibrillators,endocardial leads (e.g., FINELINE and ENDOTAK, available from AbbottVascular, Santa Clara, Calif.), clips (e.g., anastomotic clips), shunts(e.g., cerebrospinal fluid and axius coronary shunts), closure devices(e.g., arterial and patent foramen ovale closure devices), and valves(e.g., artificial heart valves).

In an embodiment, optionally in combination with one or more otherembodiments described herein, the implantable device is selected fromthe group consisting of stents, grafts, stent-grafts, catheters, leadsand electrodes, clips, shunts, closure devices, and valves. In a morespecific embodiment, optionally in combination with one or more otherembodiments described herein, the implantable device is a stent. Thestent may be balloon-expandable or self-expandable. Moreover, the stentmay be intended for any vessel in the body, e.g., neurological, carotid,vein graft, coronary, aortic renal, iliac, femoral, poplitealvasculature and urethral passages.

The underlying structure of the implantable device can be of virtuallyany design. The device can be made of a metallic material or an alloysuch as, but not limited to, cobalt-chromium alloys (e.g., ELGILOY),“L-605”, stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, tantalum-based alloys, nickel-titanium alloys, platinum,platinum-based alloys (e.g., platinum-iridium alloy), iridium, gold,magnesium, titanium, titanium-based alloys, zirconium-based alloys, orcombinations thereof. “L-605” is a trade name for an alloy of cobalt,chromium, tungsten, nickel and iron available as Haynes 25 from HaynesInternational (Kokomo, Ind.). “L-605” consists of 51% cobalt, 20%chromium, 15% tungsten, 10% nickel and 3% iron. “MP35N” and “MP20N” aretrade names for alloys of cobalt, nickel, chromium and molybdenumavailable from Standard Press Steel Co. (Jenkintown, Pa.). “MP35N”consists of 35% cobalt, 35% nickel, 20% chromium and 10% molybdenum.“MP20N” consists of 50% cobalt, 20% nickel, 20% chromium and 10%molybdenum.

Structure of Coating

According to embodiments of the invention, optionally in combinationwith one or more other embodiments described herein, a coating for animplantable device (e.g., a stent) can be a multi-layer structure thatmay include any of the following four layers or combination thereof:

-   -   (1) a primer layer;    -   (2) a drug-polymer layer (also referred to as a “reservoir” or        “reservoir layer”) or, alternatively, a polymer-free drug layer;    -   (3) a topcoat layer; and/or    -   (4) a finishing coat layer.

Each layer of a stent coating can be disposed over the stent bydissolving the polymer or a blend of polymers in a solvent, or a mixtureof solvents, and disposing the resulting polymer solution over the stentby spraying or immersing the stent in the solution. After the solutionhas been disposed over the stent, the coating is dried by allowing thesolvent to evaporate. The process of drying can be accelerated if thedrying is conducted at an elevated temperature. The complete stentcoating can be optionally annealed at a temperature between about 40° C.and about 150° C. for a period of time between about 5 minutes and about60 minutes, if desired, to improve the thermodynamic stability of thecoating.

To incorporate a drug into the reservoir layer, the drug can be combinedwith the polymer solution that is disposed over the stent as describedabove. Alternatively, if it is desirable to have the stent coating witha fast drug-release rate, a polymer-free reservoir can be made. Tofabricate a polymer-free reservoir, the drug can be dissolved in asuitable solvent or mixture of solvents, and the resulting drug solutioncan be disposed over the stent by spraying or immersing the stent in thedrug-containing solution.

Instead of introducing a drug via a solution, the drug can be introducedas a colloid system, such as a suspension in an appropriate solventphase. To make the suspension, the drug can be dispersed in the solventphase using conventional techniques used in colloid chemistry. Dependingon a variety of factors, e.g., the nature of the drug, those havingordinary skill in the art can select the solvent to form the solventphase of the suspension, as well as the quantity of the drug to bedispersed in the solvent phase. Optionally, a surfactant may be added tostabilize the suspension. The suspension can be mixed with a polymersolution and the mixture can be disposed over the stent as describedabove. Alternatively, the drug suspension can be disposed over the stentwithout being mixed with the polymer solution.

The drug-polymer layer can be applied directly onto at least a part ofthe stent surface to serve as a reservoir for at least one bioactiveagent or drug that is incorporated into the reservoir layer. Theoptional primer layer can be applied between the stent and the reservoirto improve the adhesion of the drug-polymer layer to the stent. Theoptional topcoat layer can be applied over at least a portion of thereservoir layer and serves as a rate-limiting membrane that helps tocontrol the rate of release of the drug. In one embodiment, the topcoatlayer can be essentially free from any bioactive agents or drugs. If thetopcoat layer is used, the optional finishing coat layer can be appliedover at least a portion of the topcoat layer for further control of thedrug-release rate and for improving the biocompatibility of the coating.Without the topcoat layer, the finishing coat layer can be depositeddirectly on the reservoir layer.

The process of the release of a drug from a coating having both topcoatand finishing coat layers includes at least three steps. First, the drugis absorbed by the polymer of the topcoat layer on the drug-polymerlayer/topcoat layer interface. Next, the drug diffuses through thetopcoat layer using the void volume between the macromolecules of thetopcoat layer polymer as pathways for migration. Next, the drug arrivesat the topcoat layer/finishing layer interface. Finally, the drugdiffuses through the finishing coat layer in a similar fashion, arrivesat the outer surface of the finishing coat layer, and desorbs from theouter surface. At this point, the drug is released into the surroundingtissue. Consequently, a combination of the topcoat and finishing coatlayers, if used, can serve as a rate-limiting barrier. The drug can bereleased through the degradation, dissolution, and/or erosion of thelayer.

In one embodiment, any or all of the layers of the stent coating can bemade of a biologically degradable, erodable, absorbable, and/orresorbable polymer. In another embodiment, the outermost layer of thecoating can be limited to such a polymer.

To illustrate in more detail, in a stent coating having all four layersdescribed above (i.e., the primer, the reservoir layer, the topcoatlayer and the finishing coat layer), the outermost layer is thefinishing coat layer, which is made of a polymer that is biologicallydegradable, erodable, absorbable, and/or resorbable. In this case, theremaining layers (i.e., the primer, the reservoir layer and the topcoatlayer) optionally can also be fabricated of a biologically degradablepolymer; the polymer may be the same or different in each layer.

If the finishing coat layer is not used, the topcoat layer can be theoutermost layer and is made of a biologically degradable polymer. Inthis case, the remaining layers (i.e., the primer and the reservoirlayer) optionally can also be fabricated of a biologically degradablepolymer; the polymer may be the same or different in each of the threelayers.

If neither the finishing coat layer nor the topcoat layer is used, thestent coating could have only two layers, the primer and the reservoir.In such a case, the reservoir is the outermost layer of the stentcoating and is made of a biologically degradable polymer. The primeroptionally can also be fabricated of a biologically degradable polymer.The two layers may be made from the same or different materials.

Increased rate of degradation, erosion, absorption and/or resorption ofa biologically degradable, erodable, absorbable and/or resorbablepolymer is expected to lead to an increased rate of release of a drugdue to the gradual disappearance of the polymer that forms the reservoiror the topcoat layer, or both. Through selection of an appropriatebiodegradable polymer, a stent coating can be engineered to provideeither fast or slow release of a drug, as desired. Those having ordinaryskill in the art can determine whether a stent coating having slow orfast drug-release rate is advisable for a particular drug. For example,fast release may be recommended for stent coatings loaded withantimigratory drugs, which often need to be released within 1 to 2weeks. For antiproliferative drugs, slow release may be desired (e.g.,up to 30-day release time).

Any layer of a stent coating may contain any amount of the at least oneadditional biologically absorbable polymer described above, or a blendof more than one such polymer. If less than 100% of the layer is made ofthe bioabsorbable polymer(s), other alternative polymers can comprisethe balance. Examples of alternative polymers that can be employedinclude, but are not limited to, polyacrylates, e.g., poly(butylmethacrylate), poly(ethyl methacrylate), poly(ethylmethacrylate-co-butyl methacrylate), poly(acrylonitrile),poly(ethylene-co-methyl methacrylate), poly(acrylonitrile-co-styrene)and poly(cyanoacrylates); fluorinated polymers and/or copolymers, e.g.,poly(vinylidene fluoride) and poly(vinylidene fluoride-co-hexafluoropropylene); poly(N-vinyl pyrrolidone); polydioxanone; polyorthoester;polyanhydride; poly(glycolic acid); poly(glycolic acid-co-trimethylenecarbonate); polyphosphoester; polyphosphoester urethane; poly(aminoacids); poly(trimethylene carbonate); poly(iminocarbonate);co-poly(ether-esters); polyalkylene oxalates; polyphosphazenes;biomolecules, e.g., fibrin, fibrinogen, cellulose, starch, collagen andhyaluronic acid; polyurethanes; silicones; polyesters; polyolefins;polyisobutylene and ethylene-alphaolefin copolymers; vinyl halidepolymers and copolymers, e.g., polyvinyl chloride; polyvinyl ethers,e.g., polyvinyl methyl ether; polyvinylidene chloride; polyvinylketones; polyvinyl aromatics, e.g., polystyrene; polyvinyl esters, e.g.,polyvinyl acetate; copolymers of vinyl monomers with each other andolefins, e.g., poly(ethylene-co-vinyl alcohol) (EVAL); ABS resins;poly(ethylene-co-vinyl acetate); polyamides, e.g., Nylon 66 andpolycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;polyimides; polyethers, epoxy resins; polyurethanes; rayon;rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate;cellulose acetate butyrate; cellophane; cellulose nitrate; cellulosepropionate; cellulose ethers; and carboxymethyl cellulose.

Method of Fabricating Implantable Device

Other embodiments of the invention, optionally in combination with oneor more other embodiments described herein, are drawn to a method offabricating an implantable device. In one embodiment, the methodcomprises forming the implantable device of a material containing anycombination of embodiments of the composition comprising a biodegradableABA′ copolymer. For example, the method comprises forming theimplantable device of a material comprising a composition thatoptionally has at least one dihydroxyaryl group conjugated to thepolymer ends of the triblock copolymer and optionally contains at leastone biocompatible moiety, at least one additional biologicallyabsorbable polymer, and/or at least one biologically active agent.

Under the method, a portion of the implantable device or the wholedevice itself may be formed of the material containing any combinationof embodiments of the composition comprising a biodegradable ABA′copolymer. Moreover, the method may comprise depositing over at least aportion of the implantable device a coating containing any combinationof embodiments of the composition comprising a biodegradable ABA′copolymer.

Accordingly, in an embodiment, the method comprises disposing over atleast a portion of an implantable device a coating containing anycombination of embodiments of the composition comprising a biodegradableABA′ copolymer. For example, the method comprises disposing over atleast a portion of an implantable device a coating comprising acomposition that optionally has at least one dihydroxyaryl groupconjugated to the polymer ends of the triblock copolymer and optionallycontains at least one biocompatible moiety, at least one additionalbiologically absorbable polymer, and/or at least one biologically activeagent.

The method may deposit a coating having a variety of thickness over animplantable device. In certain embodiments, the method deposits over atleast a portion of the implantable device a coating that has a thicknessof about 30 micron, or ≦about 20 micron, or ≦about 10 micron.

According to an embodiment, the method is used to fabricate animplantable device selected from the group consisting of stents, grafts,stent-grafts, catheters, leads and electrodes, clips, shunts, closuredevices, and valves. In a specific embodiment, the method is used tofabricate a stent.

The triblock copolymer of the invention, and any other desiredsubstances and materials, may be formed into a polymer construct, suchas a tube or sheet that can be rolled or bonded to form a construct suchas a tube. An implantable device may then be fabricated from theconstruct. For example, a stent can be fabricated from a tube by lasermachining a pattern into the tube. In another embodiment, a polymerconstruct may be formed from the polymeric material of the inventionusing an injection-molding apparatus.

In general, representative examples of polymers that may be used tofabricate an implantable device include, but are not limited to,poly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(L-lactide-co-glycolide),poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate),polyethylene amide, polyethylene acrylate, poly(glycolicacid-co-trimethylene carbonate), co-poly(ether-esters) (e.g., PEO/PLA),polyphosphazenes, biomolecules (e.g., fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers other than polyacrylates,vinyl halide polymers and copolymers (e.g., polyvinyl chloride),polyvinyl ethers (e.g., polyvinyl methyl ether), polyvinylidene halides(e.g., polyvinylidene chloride), polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (e.g., polystyrene), polyvinyl esters (e.g.,polyvinyl acetate), acrylonitrile-styrene copolymers, ABS resins,polyamides (e.g., Nylon 66 and polycaprolactam), polycarbonates,polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon,rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, and carboxymethyl cellulose.

Additional representative examples of polymers that may be well suitedfor fabricating an implantable device include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOH or by the trade nameEVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluoropropylene) (e.g., SOLEF 21508, available fromSolvay Solexis PVDF of Thorofare, N.J.), polyvinylidene fluoride(otherwise known as KYNAR, available from ATOFINA Chemicals ofPhiladelphia, Pa.),poly(tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene fluoride),ethylene-vinyl acetate copolymers, and polyethylene glycol.

Method of Treating or Preventing Disorders

An implantable device formed of a material or coating containing anycombination of embodiments of the composition comprising a biodegradableABA′ copolymer can be used to treat, prevent or diagnose conditions ordisorders. Examples of such conditions or disorders include, but are notlimited to, atherosclerosis, thrombosis, restenosis, hemorrhage,vascular dissection, vascular perforation, vascular aneurysm, vulnerableplaque, chronic total occlusion, patent foramen ovale, claudication,anastomotic proliferation of vein and artificial grafts, bile ductobstruction, ureter obstruction and tumor obstruction.

Accordingly, an embodiment of the invention, optionally in combinationwith one or more other embodiments described herein, is drawn to amethod of treating, preventing or diagnosing a condition or disorder ina patient, comprising implanting in the patient an implantable deviceformed of a material or coating containing any combination ofembodiments of the composition comprising a biodegradable ABA′copolymer. For example, the implantable device may be formed of amaterial or coating comprising a composition that optionally has atleast one dihydroxyaryl group conjugated to the polymer ends of thetriblock copolymer and optionally contains at least one biocompatiblemoiety, at least one additional biologically absorbable polymer, and/orat least one biologically active agent.

In one embodiment, the implantable device is formed of a material orcoating containing at least one biologically active agent selected fromthe group consisting of paclitaxel, docetaxel, estradiol, nitric oxidedonors, super oxide dismutases, super oxide dismutase mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N-1-tetrazolyl)-rapamycin (zotarolimus), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, progenitor cell-capturing antibodies,prohealing drugs, prodrugs thereof, co-drugs thereof, and a combinationthereof.

In an embodiment, the implantable device used in the method is selectedfrom the group consisting of stents, grafts, stent-grafts, catheters,leads and electrodes, clips, shunts, closure devices, and valves. In aspecific embodiment, the implantable device is a stent.

According to one embodiment, the condition or disorder treated,prevented or diagnosed by the implantable device is selected from thegroup consisting of atherosclerosis, thrombosis, restenosis, hemorrhage,vascular dissection, vascular perforation, vascular aneurysm, vulnerableplaque, chronic total occlusion, patent foramen ovale, claudication,anastomotic proliferation of vein and artificial grafts, bile ductobstruction, ureter obstruction and tumor obstruction.

Synthesis of Triblock Copolymers

The triblock copolymers of the invention can be prepared by any methodof polymerization known in the art. Methods of polymerization include,but are not limited to, solution-based polymerization and melt-phasepolymerization. In solution-based polymerization, all the reactivecomponents involved in the polymerization reaction are dissolved in asolvent.

In some embodiments of solution-based polymerization, monomer units ofthe blocks, an initiator, a catalyst and at least one solvent are used.The first step generally involves forming a precursor block, e.g., the Bblock. Monomer units of the precursor block, a suitable initiator and asuitable catalyst are added to a suitable solvent to form apolymerization solution. After formation of the precursor block, monomerunits of the second block (e.g., the A block, or the A and A′ blocks ifthese two blocks are the same) and a catalyst (which may be the same ordifferent than the catalyst used in the first reaction) are then addedto the solution to form an AB diblock copolymer or an ABA′ triblockcopolymer (if the A and A′ blocks are the same). If the A and A′ blocksare different, then a third reaction to form the A′ block may proceed ina similar manner as the second reaction to form the A block. Thesolvent(s) in the reaction(s) for forming the A and A′ blocks can beselected so that the precursor block is soluble in the solvent(s) forthe second reaction and the AB diblock is soluble in the solvent(s) forthe third reaction, which would facilitate copolymerization of theprecursor block and AB diblock with the added units of the A block andthe A′ block, respectively. In an embodiment, the B block is formedfirst in the synthesis of a triblock copolymer.

Triblock copolymers can be synthesized by standard methods known tothose having ordinary skill in the art, e.g., by ring-openingpolymerization (ROP) with the corresponding monomers of the blocks. ROPcan be catalyzed by an organic or inorganic acid (including a Lewisacid), an organic or inorganic base (including a Lewis base), anorganometallic reagent, and/or heat, if necessary.

One method of synthesizing A-B-A′ triblock copolymers of the inventionis to conduct ring-opening polymerization (ROP) with the correspondingmonomer(s) of the A, B and A′ blocks. For example, triblock copolymersin which the A and A′ blocks are the same may be produced by performingROP with the corresponding monomer(s) of the B block, and thenperforming ROP with the corresponding monomer(s) of the A and A′ blocks.An initiating compound containing two active end groups is employed toinitiate ROP with the first monomer of the B block. In an embodiment,the two active end groups on the initiating compound are independently ahydroxyl, amino or thiol group.

Likewise, A-B-A′ triblock copolymers in which the A and A′ blocks aredifferent may be synthesized by:

-   -   performing ROP with the corresponding monomer(s) of the B block,        wherein an initiating compound containing one active end group        and one protected end group is used to initiate ROP with the        first monomer of the B block;    -   performing ROP with the corresponding monomer(s) of the A block;    -   protecting any active group formed at the polymer end of the A        block;    -   deprotecting the protected end group derived from the initiating        compound at the polymer end of the B block;    -   performing ROP with the corresponding monomer(s) of the A′        blocks; and then    -   optionally deprotecting the protected active group at the        polymer end of the A block.        In an embodiment, the active end group on the initiating        compound is a hydroxyl, amino or thiol group, and the protected        end group on the initiating compound is a protected hydroxyl,        amino or thiol group.

In some embodiments, the initiating compounds employed in the synthesisof the triblock copolymers have at least one active end group that is ahydroxyl, amino or thiol group. In an embodiment, the initiatingcompound is a diol, in which one of the hydroxyl end groups mayoptionally be protected. In another embodiment, the initiating compoundis a diamine, in which one of the amino end groups may optionally beprotected. In yet another embodiment, the initiating compound is adithiol, in which one of the thiol end groups may optionally beprotected. In further embodiments, the diamino, dithiol or dihydroxyinitiating compound is C₂-C₂₄ and contains an optionally substitutedaliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic,aromatic or heteroaromatic group, or a combination thereof. In otherembodiments, the initiating compound is a diol selected from diethyleneglycol, triethylene glycol, tetraethylene glycol, poly(ethylene glycol),poly(propylene glycol), poly(tetramethylene glycol), andpoly(caprolactone) diol.

One example of the synthesis of A-B-A′ triblock copolymers, in which theA and A′ blocks are the same, via ROP is illustrated by the synthesis ofpoly(D,L-lactide-co-glycolide-bl-trimethylenecarbonate-bl-glycolide-co-D,L-lactide) via ROP in Scheme 1 below.

In Scheme 1, 1,6-hexanediol is employed to initiate ROP with TMC. Theresulting bis(hydroxyl)-terminated B block, PTMC, can then be used toinitiate ROP with glycolide, leading to the formation ofbis(hydroxyl)-terminated PGA-bl-PTMC-bl-PGA. The A and A′ blocks arefurther elaborated via ROP of this intermediate with a different type ofmonomer, D,L-lactide, resulting in the triblock copolymer,poly(D,L-lactide-co-glycolide)-block-poly-(trimethylenecarbonate)-block-poly(glycolide-co-D,L-lactide). In this example, the Aand A′ blocks are the same (i.e., poly(glycolide-co-D,L-lactide)), andm, n and p each independently are integers from about 5 to about 5,000.A person of ordinary skill in the art would understand that thesynthetic procedure in the above example could also be modified togenerate poly(D,L-lactide-ran-glycolide)-block-poly-(trimethylenecarbonate)-block-poly(glycolide-ran-D,L-lactide) by conducting ROP inthe presence of glycolide and D,L-lactide in the same pot.

The synthesis of triblock copolymers is often done neat, in the absenceof a solvent. However, the blocks are not always miscible with eachother. For example, in the melt the glycolide may not dissolve in thePTMC polymer. In such a case, polymerization would be conducted in asolvent. If done properly, the intermediate bis(hydroxyl)-terminatedPTMC polymer would not need to be isolated and could be used to initiatethe next ROP with glycolide.

In the synthesis of a polymer containing a high content of glycolide, astrong or exotic solvent may be needed to initially dissolve themonomer(s). A solvent can usually be employed to dissolve a mixture ofmonomers into a mixture of monomers and then be evaporated off before aninitiating catalyst is added to start the polymerization. The soft Bblock may also assist in the dissolution of the monomers of the A and A′blocks. In addition, various organo and organometallic catalysts mayinfluence the structure of the polymer by providing different releasekinetics and minimize or maximize the polymerization rate of the variousmonomers incorporated into the A, B or A′ block.

The various embodiments of the inventive composition comprising anA-B-A′ triblock copolymer, whether the A and A′ blocks are the same ordifferent, may be prepared by optionally:

-   -   conjugating at least one dihydroxyaryl group to the polymer ends        of the triblock copolymer;    -   blending or bonding at least one biocompatible moiety with the        triblock copolymer;    -   blending or bonding at least one additional biologically        absorbable polymer with the triblock copolymer; and    -   incorporating at least one biologically active agent.

The at least one dihydroxyaryl group may contain, e.g., anortho-dihydroxyphenyl moiety such as 1,2-dihydroxyphenyl and3,4-dihydroxyphenyl. 3,4-Dihydroxyphenyl-containing compounds include,e.g., dopamine and 3,4-dihydroxyhydrocinnamic acid. Dopamine could beconjugated to hydroxyl end groups of a triblock copolymer via couplingwith 1,1′-carbonyldiimidazole. 3,4-Dihydroxy-hydrocinnamic acid could beconjugated to hydroxyl end groups by conversion of the cinnamic acid tothe N-succidimyl ester or by use of dicyclohexylcarbodiimide (DCC) and4-(dimethylamino)pyridinium (DPTS). Alternatively, conjugation of thecinnamic acid could be effected via a Mitsunobu reaction usingtriphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD).

EXAMPLES

The examples set forth below are shown for the sole purpose of furtherillustrating embodiments of the present invention and are in no waymeant to limit the invention. The following prophetic examples are givento aid in understanding the invention, but it is to be understood thatthe invention is not limited to the particular materials or proceduresof the examples.

Example 1 Synthesis ofPoly(glycolide-ran-D,L-lactide)-block-poly(TMC)-block-poly(glycolide-ran-D,L-lactide),51.8 mole % glycolide, 43.6 mole % trimethylene carbonate, and 4.6 mole% D,L-lactide

A flame-dried, three-neck 250 ml round-bottom flask is charged with46.41 g (0.455 mole) trimethylene carbonate, 0.123 g (1.16 mmol)distilled diethylene glycol, and 0.053 ml of stannous octoate (0.33 M intoluene) (60,000:1 molar ratio monomer:catalyst). The flask is equippedwith a flame-dried mechanical stirrer and adapter for argon purge andvacuum. The reaction vessel is purged by evacuating the flask, followedby venting with argon; this is repeated three times. The reaction flask,under an argon pressure of one atmosphere, is heated to 190° C. andmaintained at this temperature for about 16 hours with slow stirring.

In the second stage of polymerization, 6.96 g (48.3 mmol) ofD,L-lactide, and 62.64 g (0.54 mole) of molten glycolide, are added tothe prepolymer in the reaction flask at 180° C. under a purge of argon.The temperature of the reaction mixture is raised to 230° C. to dissolvethe prepolymer into the molten glycolide with gentle stirring. After tenminutes, the temperature is dropped to 200° C. and held there for abouttwo hours with stirring. The polymer is removed from the reactor as amelt and allowed to cool. After grinding, the polymer is dried byheating at 110° C. under a pressure of 0.1 mm Hg for 16 hours to removeany unreacted monomers.

Example 2 Synthesis ofPoly(D,L-lactide)-block-poly(caprolactone-ran-glycolide)-block-poly(D,L-lactide),39.5 mole % caprolactone, 34.7 mole % D,L-lactide, and 25.8 mole %glycolide

A flame-dried, three-neck, 250 ml round-bottom flask is charged with36.0 g (0.316 mole) caprolactone and 24.0 g (0.207 mole) glycolide. Theflask is equipped with a flame-dried mechanical stirrer and adapter forargon purge and vacuum. The contents are heated to 120° C. and stirredunder vacuum for four hours. After purging with argon, and cooling toroom temperature, 0.11 gm (1.4 mmol) distilled diethylene glycol, and0.097 ml of stannous octoate (0.33 M in toluene) (25,000:1 molar ratiomonomer:catalyst), are added. The reaction vessel is purged byevacuating the flask followed by venting with argon; this is repeatedthree times. The reaction flask, under an argon pressure of oneatmosphere, is heated to 180° C. and maintained at this temperature forabout 24 hours with slow stirring.

In the second stage of polymerization, 40.0 g (0.278 mole) ofD,L-lactide is added to the prepolymer in the reaction flask at 180° C.under a purge of argon. The temperature is raised to 200° C. and heldthere for about two hours with stirring. The polymer is removed from thereactor as a melt and allowed to cool. After grinding, the polymer isdissolved in chloroform and then precipitated in methanol. Solvent,unreacted monomer, and water are removed by heating the precipitate at110° C. under a pressure of 0.1 mm Hg for 16 hours.

Example 3 Method of Manufacturing a Drug-Delivery Stent Coating Usingthe Copolymer of Example 1 or 2

In a first step, an optional primer coating is applied to a stent. Aprimer solution containing between about 0.1 mass % and about 15 mass %,(e.g., about 2.0 mass %) of the copolymer of Example 1 or 2, and thebalance being a solvent mixture of chloroform and 1,1,1-trichloroethane(having about 50 mass % of chloroform and about 50 mass % of1,1,1-trichloroethane) is prepared. The solution is applied onto thestent to form a primer layer.

To apply the primer layer, a spray apparatus (e.g., Sono-Tek MicroMistspray nozzle, manufactured by Sono-Tek Corp. of Milton, N.Y.) is used.The spray apparatus is an ultrasonic atomizer with a gas entrainmentstream. A syringe pump is used to supply the coating solution to thenozzle. The composition is atomized by ultrasonic energy and applied tothe stent surfaces. A useful nozzle-to-stent distance is about 20 mm toabout 40 mm at an ultrasonic power of about one watt to about two watts.During the process of applying the composition, the stent is optionallyrotated about its longitudinal axis, at a speed of about 100 to about600 rpm, e.g., about 400 rpm. The stent is also linearly moved along thesame axis during the application.

The primer solution is applied to a 3.0×12 mm VISION™ stent (availablefrom Abbott Vascular Corp.) in a series of 20-second passes, to deposit,e.g., 20 μg of coating per spray pass. Between the spray passes, thestent is allowed to dry for about 10 seconds to about 30 seconds atambient temperature. Four spray passes can be applied, followed bybaking the primer layer at about 80° C. for about 1 hour. As a result, aprimer layer can be formed having a solids content of about 80 μg. Forpurposes of this example, “solids” means the amount of the dry residuedeposited on the stent after all volatile organic compounds (e.g., thesolvent) have been removed.

In a manner similar to the application of the primer layer, apolymer-therapeutic solution is prepared and applied using the followingformula:

-   -   (a) between about 0.1 mass % and about 15 mass %, (e.g., about        2.0 mass %) of the copolymer of Example 1 or 2;    -   (b) between about 0.1 mass % and about 2 mass % (e.g., about 1.0        mass %) of a therapeutic agent. In one embodiment, the        therapeutic agent is everolimus (available from Abbott Vascular        Corp. of Santa Clara, Calif.); and    -   (c) the balance, a solvent mixture containing about 50 mass % of        chloroform and about 50 mass % of 1,1,1-trichloroethane.

The drug-containing formulation is applied to the stent in a mannersimilar to the application of the copolymer primer layer. The processresults in the formation of a drug-polymer reservoir layer having asolids content between about 30 μg and about 750 μg, (e.g., about 175μg) and a drug content of between about 10 μg and about 250 μg, (e.g.,about 55 μg). After application, the coating is baked at 50° C. for twohours to remove any remaining solvent.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made thereto without departing from theinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of the present invention.

1. A composition comprising a biodegradable triblock copolymer of thestructure A-B-A′, wherein: the A and A′ blocks each independently arehard blocks having a T_(g) or T_(m) above body temperature; the B blockis a soft block having a T_(g) less than the T_(g) or T_(m) of the A andA′ blocks; the A, B and A′ blocks each independently have a polymernumber-average molecular weight (M_(n)) from about 1 kDa to about 500kDa; and the A and A′ blocks may be the same or different.
 2. Thecomposition of claim 1, wherein the tensile modulus of the hard A and A′blocks independently is greater than about 1,000 MPa, and the tensilemodulus of the soft B block is less than about 1,000 MPa.
 3. Thecomposition of claim 1, wherein the weight fraction of the A and A′blocks is from about 1% to about 99% of the triblock copolymer.
 4. Thecomposition of claim 1, wherein the A, B and A′ blocks eachindependently comprise a polymer comprising from one to four differenttypes of monomer, wherein each type of monomer has from about 5 to about5,000 monomer units.
 5. The composition of claim 1, wherein the A and A′blocks are the same.
 6. The composition of claim 1, wherein the A and A′blocks are different.
 7. The composition of claim 1, wherein: the A andA′ blocks each independently comprise a polymer selected from the groupconsisting of poly(L-lactide) (PLLA), poly(D,L-lactide), poly(glycolide)(PGA), poly(GA-co-D,L-lactide), poly(GA-co-L-lactide), and anyvariations in the arrangement of the monomers thereof; and the B blockcomprises a polymer selected from the group consisting ofpoly(caprolactone) (PCL), poly(CL-co-GA), poly(trimethylene carbonate)(PTMC), poly(TMC-co-GA), poly(TMC-co-D,L-lactide),poly(TMC-co-L-lactide), poly(TMC-co-CL), poly(TMC-co-D,L-lactide-co-GA),poly(TMC-co-CL-co-GA), poly(dioxanone), poly(TMC-co-dioxanone),poly(dioxanone-co-CL), poly(dioxanone-co-D,L-lactide),poly(dioxanone-co-L-lactide), poly(dioxanone-co-GA),poly(dioxanone-co-D,L-lactide-co-GA), polyketals, and any variations inthe arrangement of the monomers thereof.
 8. The composition of claim 7,wherein the polyketal polymer of the B block has the structure of

wherein R₁ is a poly(caprolactone) diol or a C₂-C₂₄ diol of thestructure, HO—R₁—OH, that contains an optionally substituted aliphatic,heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic orheteroaromatic group, or a combination thereof, and n is an integer fromabout 5 to about 5,000.
 9. The composition of claim 1, wherein the Bblock is immiscible with the A and A′ blocks.
 10. The composition ofclaim 1, further comprising at least one dihydroxyaryl group conjugatedto the polymer ends of the triblock copolymer.
 11. The composition ofclaim 10, wherein the at least one dihydroxyaryl group contains a3,4-dihydroxyphenyl moiety.
 12. The composition of claim 1, furthercomprising at least one biocompatible moiety.
 13. The composition ofclaim 12, wherein the at least one biocompatible moiety is selected fromthe group consisting of poly(ethylene oxide), poly(propylene glycol),poly(tetramethylene glycol), polyethylene oxide-co-propylene oxide),ε-caprolactone, β-butyrolactone, δ-valerolactone, glycolide,poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid)and salts thereof, poly(styrene sulfonate), sulfonated dextran,polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), sialicacid, hyaluronic acid or derivatives thereof, copolymers ofpoly(ethylene glycol) with hyaluronic acid or derivatives thereof,heparin, copolymers of polyethylene glycol with heparin, a graftcopolymer of poly(L-lysine) and poly(ethylene glycol), and copolymersthereof.
 14. The composition of claim 1, further comprising at least oneadditional biologically absorbable polymer.
 15. The composition of claim14, wherein the at least one additional biologically absorbable polymeris selected from the group consisting of poly(hydroxybutyrate),poly(hydroxyvalerate), poly(hydroxybutyrate-co-valerate),poly(caprolactone), poly(lactide-co-glycolide),poly(ethylene-glycol)-block-poly(butyleneterephthalate),poly(ethylene-glycol)-block-poly(butyleneterephthalate)-block-polyethylene-glycol),poly(butyleneterephthalate)-block-poly(ethylene-glycol)-blockpoly(butyleneterephthalate),poly(ethylene-glycol)-block-poly(caprolactone),poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol),poly(caprolactone)-block-poly(ethylene-glycol)-block-poly(caprolactone),and blends thereof.
 16. The composition of claim 1, further comprisingat least one biologically active agent selected from the groupconsisting of antiproliferative, antineoplastic, antimitotic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antibiotic, antiallergic and antioxidant substances. 17.The composition of claim 16, wherein the at least one biologicallyactive agent is selected from the group consisting of paclitaxel,docetaxel, estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(2-ethoxy)ethyl-rapamycin (biolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N-1-tetrazolyl)-rapamycin (zotarolimus), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, progenitor cell-capturing antibodies,prohealing drugs, prodrugs thereof, co-drugs thereof, and a combinationthereof.
 18. A coating comprising the composition of claim
 1. 19. Thecoating of claim 18, which has a thickness of ≦about 10 micron and losesabout 100% of its mass within about 12 months.
 20. A coating comprisingthe composition of claim
 10. 21. A coating comprising the composition ofclaim
 12. 22. A coating comprising the composition of claim
 14. 23. Acoating comprising the composition of claim
 16. 24. The coating of claim23, which has a thickness of ≦about 10 micron and loses about 100% ofits mass within about 12 months.
 25. A coating comprising thecomposition of claim
 17. 26. An implantable device formed of a materialcomprising the composition of claim
 1. 27. The device of claim 26,wherein the material is a coating disposed over the device.
 28. Thedevice of claim 27, wherein the coating has a thickness of ≦about 10micron and loses about 100% of its mass within about 12 months.
 29. Thedevice of claim 26, which is selected from the group consisting ofstents, grafts, stent-grafts, catheters, leads and electrodes, clips,shunts, closure devices, and valves.
 30. An implantable device formed ofa material comprising the composition of claim
 10. 31. An implantabledevice formed of a material comprising the composition of claim
 12. 32.An implantable device formed of a material comprising the composition ofclaim
 14. 33. An implantable device formed of a material comprising thecomposition of claim
 16. 34. The device of claim 33, wherein thematerial is a coating disposed over the device.
 35. The device of claim34, wherein the coating has a thickness of ≦about 10 micron and losesabout 100% of its mass within about 12 months.
 36. The device of claim33, which is selected from the group consisting of stents, grafts,stent-grafts, catheters, leads and electrodes, clips, shunts, closuredevices, and valves.
 37. The device of claim 36, which is a stent. 38.An implantable device formed of a material comprising the composition ofclaim
 17. 39. A method of preparing the composition of claim 5,comprising: performing ring-opening polymerization (ROP) with thecorresponding monomer(s) of the B block, wherein an initiating compoundcontaining two active end groups is used to initiate ROP with the firstmonomer of the B block, and wherein the two active end groups on theinitiating compound are independently a hydroxyl, amino or thiol group;and performing ROP with the corresponding monomer(s) of the A and A′blocks.
 40. A method of preparing the composition of claim 6,comprising: performing ring-opening polymerization (ROP) with thecorresponding monomer(s) of the B block, wherein an initiating compoundcontaining one active end group and one protected end group is used toinitiate ROP with the first monomer of the B block, and wherein theactive end group on the initiating compound is a hydroxyl, amino orthiol group, and the protected end group on the initiating compound is aprotected hydroxyl, amino or thiol group; performing ROP with thecorresponding monomer(s) of the A block; protecting any active groupformed at the polymer end of the A block; deprotecting the protected endgroup derived from the initiating compound at the polymer end of the Bblock; performing ROP with the corresponding monomer(s) of the A′blocks; and optionally deprotecting the protected active group at thepolymer end of the A block.
 41. A method of fabricating an implantabledevice, comprising forming the device of a material comprising thecomposition of claim
 1. 42. The method of claim 41, comprisingdepositing the material as a coating over at least a portion of theimplantable device.
 43. The method of claim 41, wherein the implantabledevice is selected from the group consisting of stents, grafts,stent-grafts, catheters, leads and electrodes, clips, shunts, closuredevices, and valves.
 44. A method of fabricating an implantable device,comprising forming the device of a material comprising the compositionof claim
 16. 45. The method of claim 44, comprising depositing thematerial as a coating over at least a portion of the implantable device.46. The method of claim 44, wherein the implantable device is selectedfrom the group consisting of stents, grafts, stent-grafts, catheters,leads and electrodes, clips, shunts, closure devices, and valves.
 47. Amethod of treating or preventing a condition or disorder in a patient,comprising implanting in the patient the implantable device of claim 26,wherein the condition or disorder is selected from the group consistingof atherosclerosis, thrombosis, restenosis, hemorrhage, vasculardissection, vascular perforation, vascular aneurysm, vulnerable plaque,chronic total occlusion, patent foramen ovale, claudication, anastomoticproliferation of vein and artificial grafts, bile duct obstruction,ureter obstruction and tumor obstruction.
 48. The method of claim 47,wherein the implantable device is selected from the group consisting ofstents, grafts, stent-grafts, catheters, leads and electrodes, clips,shunts, closure devices, and valves.
 49. A method of treating orpreventing a condition or disorder in a patient, comprising implantingin the patient the implantable device of claim 33, wherein the conditionor disorder is selected from the group consisting of atherosclerosis,thrombosis, restenosis, hemorrhage, vascular dissection, vascularperforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, patent foramen ovale, claudication, anastomotic proliferationof vein and artificial grafts, bile duct obstruction, ureter obstructionand tumor obstruction.
 50. The method of claim 49, wherein theimplantable device is selected from the group consisting of stents,grafts, stent-grafts, catheters, leads and electrodes, clips, shunts,closure devices, and valves.